Anti-IFNAR1 Dosage Regimen for Subcutaneous Injection

Abstract

To provide methods and compositions for treatment of type I IFN mediated disease, and specifically, an autoimmune disease such as systemic lupus erythematosus and lupus nephritis.SOLUTION: A method comprises subcutaneously administering once weekly to a subject a pharmaceutical composition comprising a unit dose containing more than (>) 105 mg and less than (<) 150 mg of a type I IFN receptor (IFNAR1) inhibitor, specifically a human monoclonal antibody specific for IFNAR1, and further specifically anifrolumab.SELECTED DRAWING: None

Description

[Background technology]

[0001] To date, clinical studies of the type I IFN receptor (IFNAR1) inhibitor anifrolumab have primarily focused on treating type 1 interferon-mediated diseases, such as systemic lupus erythematosus (SLE), with intravenous (IV) administration of the antibody. However, intravenous administration requires patients to visit a hospital or clinic so that the procedure can be performed by a medical professional. As such, intravenous administration is inconvenient for patients and places a burden on both patients and the healthcare system.

[0002] 1.1. Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a chronic, multisystem, disabling autoimmune rheumatic disease of unknown etiology. There is a significant unmet medical need for the treatment of SLE, particularly in patients with moderate or severe disease. Long-term prognosis remains poor for many patients. In the nearly 60 years since hydroxychloroquine was approved for use in discoid lupus and SLE, only one new treatment for SLE (belimumab) has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Many medications currently used to treat SLE, such as azathioprine, cyclophosphamide, and mycophenolate mofetil / mycophenolic acid, are not approved for the disease. Furthermore, all of these medications have well-documented safety issues and are not effective against all manifestations of lupus in all patients. Glucocorticoids remain the primary treatment, with doses varying depending on the severity of disease manifestations. Regarding the risk of developing glucocorticoid-induced disorders such as cataracts, osteoporosis, and coronary artery disease, there is no "safe" dose of oral glucocorticoids, and while exposure to high doses of glucocorticoids has been shown to be associated with increased overall incidence of disorders, even very low to moderate doses may be associated with increased disorders.

[0003] Clinical manifestations of SLE include, but are not limited to, systemic symptoms such as fatigue and fever, alopecia, rash, serositis, arthritis, nephritis, vasculitis, lymphadenopathy, splenomegaly, hemolytic anemia, cognitive dysfunction, and other nervous system disorders. These disease manifestations create a significant burden of illness and can lead to permanent organ damage, physical disability, unemployment, and a significant decrease in health-related quality of life (QoL). Increased hospitalization and side effects of drug therapies, including long-term high-dose glucocorticoids and other immunosuppressive therapies, significantly increase the disease burden of SLE. All of the currently used therapies for the treatment of SLE have well-known adverse effect profiles, and there is a medical need to identify new targeted therapies, particularly agents that can reduce the required doses of glucocorticoids and cytotoxic agents.

[0004] Subcutaneous administration Compared to the intravenous route, subcutaneous administration has the advantage of allowing administration at home, thus reducing the frequency of patient visits to the hospital. Subcutaneous (SC) administration is therefore particularly advantageous during a global pandemic, such as the SARS-Cov2 pandemic, to avoid the need for potentially immunocompromised patients to visit the hospital and thereby expose them to the risk of SARS-Cov2 infection.

[0005] Although subcutaneous administration offers advantages over intravenous injection, switching from intravenous to subcutaneous administration is challenging. Conversion to subcutaneous administration may require the development of novel formulations and consideration of factors such as differences in bioavailability, pharmacokinetic properties, and immunogenicity of subcutaneous administration compared with intravenous administration [1].

[0006] The pharmacokinetic profiles of subcutaneous and intravenous formulations differ. When monoclonal antibodies are injected directly into the bloodstream, they usually reach a rapid maximum serum concentration (C maxIn contrast, the pharmacokinetic (PK) profile of therapeutic proteins injected subcutaneously typically exhibits slower absorption rates and lower C values ​​than those obtained with intravenous administration. max Subcutaneous administration is characterized by low bioavailability levels [2]. Furthermore, subcutaneous administration results in poor bioavailability of injected molecules, which can range widely from 50 to 80% in the case of mAbs [2]. This poor bioavailability typically necessitates higher subcutaneous doses than intravenous infusions. Therefore, predicting the PK of therapeutically administered SCs is difficult [2].

[0007] Predicting a safe and therapeutically effective subcutaneous dose based on intravenous doses is particularly challenging in heterogeneous autoimmune diseases such as lupus (e.g., SLE). The difficulty of predicting a safe and effective subcutaneous dose for the treatment of SLE using data from intravenous administration of biologics has been demonstrated by past failed attempts. For example, in a phase 1 study of SLE, a single dose of tabalumab (an anti-BAFF monoclonal antibody) was administered intravenously to a total of five SLE patients [3]. In the subsequent phase 3 ILLUMINATE trials (NCT01205438 and NCT01196091), subcutaneous administration was chosen instead of the intravenous route [4, 5]. In the phase 1 study, SLE patients received a single intravenous dose of tabalumab at either 0.125 mg / kg or 2.0 mg / kg [3]. In the Phase 3 ILLUMINATE trial, subjects received an initial subcutaneous loading dose of 240 mg, followed by 120 mg subcutaneously either twice weekly or monthly. The primary endpoint, SRI-5 response, was not met in either dose group. The investigators commented that a possible reason for the trial's failure was the selection of an inappropriate SC dose [4], and that the optimal SC dose was unclear according to the trial [5].

[0008] 1.3. Anifrolumab Anifrolumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) directed against subunit 1 of the type 1 interferon receptor (IFNAR1). Although subcutaneous administration offers advantages over intravenous administration, a safe and effective subcutaneous dose of anifrolumab in patients with SLE has not previously been determined.

[0009] The present invention solves one or more of the above problems by providing a dose of an IFNAR1 inhibitor (e.g., anifrolumab) for subcutaneous administration. Summary of the Invention [Means for solving the problem]

[0010] The present invention relates to a subcutaneous dose of a type I IFN receptor (IFNAR1, also known as IFNAR). The present invention also relates to a subcutaneous dose of an IFNAR1 inhibitor for use in a method of treating a type I IFN-mediated disease, such as lupus (e.g., SLE), in a subject. The present invention is supported by data showing that a common type I IFN gene signature (IFNGS) is elevated in subjects with type I IFN-mediated diseases, including lupus, myositis, scleroderma, and Sjogren's syndrome, that this IFNGS is associated with disease severity, and the identification of a safe and effective dose of an IFNAR1 inhibitor that neutralizes IFNGS.

[0011] The present invention is supported by efficacy, safety, and PK data for the IFNAR1 inhibitor (anifrolumab) from, inter alia, two Phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials in SLE patients (NCT02446899 and NCT02962960), a Phase 2, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in SLE patients (NCT02962960), a Phase 1, randomized, placebo-controlled, double-blind clinical trial in health subjects (NCT02601625), and a Phase 2 study to characterize the pharmacokinetics, pharmacodynamics, and safety of anifrolumab in type 1 interferon-competent adult SLE subjects (NCT02962960), analyses of which are presented herein for the first time. Using innovative data modeling, the inventors identified an optimal subcutaneous dose of an IFNAR1 inhibitor that provides equivalent safety and efficacy to the intravenous dose. [Brief explanation of the drawings]

[0012] [Figure 1] Study design for TULIP-1 and TULIP-2: ACR: American College of Rheumatology; ANA: antinuclear antibody; anti-dsDNA: anti-double-stranded DNA; anti-Sm: anti-Smith antibody; BICLA: BILAG-based combined lupus assessment; BILAG: British Isles Lupus Assessment Group; IFNGS: interferon gene signature; IV: intravenous; OCS: oral corticosteroid; PGA: physician's global assessment; Q4W: once every 4 weeks; SLE: systemic lupus erythematosus; SLEDAI-2K: SLE Disease Activity Index 2000; SRI(4): SLE responder index. aEligible patients met the ACR SLE classification; bPatients were stratified by IFNGS status, SLEDAI-2K score, and OCS dosage; cFor patients with baseline OCS of prednisone ≥ 10 mg / day or equivalent. [Figure 2]Efficacy results for TULIP-1 and TULIP-2. Overall efficacy results for TULIP-1, TULIP-2, and MUSE. BICLA: BILAG-based composite lupus assessment; BILAG: British Isles Lupus Assessment Group; CI: confidence interval; CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; IFNGS: interferon gene signature; OCS: oral corticosteroids; SRI(4): SLE responder index. Analytical methods and definitions varied between studies. Published data are expressed as odds ratios; b previously unpublished data. [Figure 3] Study 05, BICLA Response Over Time and Time to First Flare. Figure 3A shows the percentage of patients with a British Isles Lupus Assessment Group (BILAG)-based Integrated Lupus Assessment (BICLA) response. Vertical bars indicate 95% confidence intervals (CI). Figure 3B shows the time to first flare, where a flare is defined as at least one new BILAG 2004 Index (BILAG-2004) A item or at least two new BILAG-2004 B items compared to the previous visit. The BILAG-2004 is an assessment of 97 clinical and laboratory variables covering nine organ systems, with scores ranging from A (severe) to E (unaffected) for each organ system. Open circles in the panels indicate censored data. Time to first flare was assessed using a Cox proportional hazards model; however, no adjustment for multiple comparisons was made, and no inferences can be drawn from these results. [Figure 4] Mean Anifrolumab Concentration Versus Shingles Incidence Incidence (%) of Shingles in Study 1013 Patients Received Placebo, 300 mg IV Anifrolumab, or 1000 mg IV Anifrolumab. [Figure 5]Mean anifrolumab serum concentration-time profiles. Figure 5A: Study MI-CP180 in SSc - Mean anifrolumab serum concentration-time profiles after a single IV dose. Data represent + / - SD. Mean data below the LLOQ are not plotted. IV; intravenous; LLOQ: lower limit of quantification; MEDI546: anifrolumab; n: number of patients in subgroup; SSc: systemic sclerosis. Figure 5B: Study 06 in healthy volunteers - Mean anifrolumab serum concentration-time profiles after a single SC and IV dose. Samples with actual collection times that deviated >10% from the nominal collection times were excluded from the averages. IV: intravenous; N: number of subjects; SC: subcutaneous. [Figure 6] Study design and results of Study 08. Figure 6A: Phase 2 study design of SC anifrolumab in patients with SLE. Study 08 (NCT02962960) evaluated the effects of two anifrolumab doses administered weekly. Figure 6B: Mean serum concentrations of anifrolumab over time. Figure 6C: Anifrolumab neutralization of the type I IFN gene signature. [Figure 7] Figure 7A: Calculated median AUC ratios (SC / IV) from weeks 0 to 52 for various SC doses. Calculated median AUC ratios (SC / IV) based on estimated bioavailability from Study 06 from weeks 0 to 52 (subcutaneous doses were either 75 mg (+ symbol), 90 mg (open squares), 105 mg (circles), 120 mg (triangles), or 135 mg (filled squares)). Here, the subcutaneous dose is administered once every seven days (QW), and the IV dose is administered once every four weeks (Q4W) at a 300 mg dose. Based on AUC, both 90 and 105 mg SC QW appear similar to 300 mg IV. Figure 7B: Calculated median AUC ratios (SC / IV) for 90 mg and 105 mg SC QW. Median AUC ratio (SC / IV) calculated based on estimated bioavailability approximately 7% lower than the bioavailability calculated from Study 06 between weeks 0 and 52 (subcutaneous doses were either 90 mg SC QW or 105 mg SC). [Figure 8]Figure 8A: Plot showing the (calculated) trough plasma concentrations of anifrolumab in patients receiving either (i) 105 mg subcutaneous anifrolumab once every 7 days (straight line), (ii) 300 mg intravenous anifrolumab once every 4 weeks (bottom dotted line), or (ii) 1000 mg intravenous anifrolumab once every 4 weeks (top dotted line). The shaded area represents the area between the 5th and 95th percentiles for the 300 mg IV Q4W dose. Figure 8B: Anifrolumab trough concentrations in SLE subjects with high IFNGS. The calculated trough concentrations of anifrolumab in plasma of patients with high IFNGS after dosing were as follows: (i) 300 mg IV Q4W, (ii) 90 mg SC QW, (iii) 105 mg SC QW, (iv) 135 mg SC QW, and (v) 1000 mg IV Q4W. SC = subcutaneous. Based on the trough, both 90 mg and 105 mg SC QW were predicted to have greater PD suppression than 300 mg IV. [Figure 9] Positive Exposure-BICLA Relationship Observed with TULIP1 and TULIP2 in Patients with High IFNGS. Figure 9A: TULIP I vs. placebo, 150 mg, and 300 mg anifrolumab. Figure 9B: TULIP II vs. placebo and 300 mg. [Figure 10] BICLA dose response. Figure 10A: Dose-response curve for the likelihood of meeting BICLA response criteria (in patients with high IFNGS) for anifrolumab Cave over 52 weeks, showing the predicted mean (gray line) and 95% confidence interval (CI) (dashed area). Patients are grouped by dose (150 mg, n=62; 300 mg, n=242; and 1000 mg). Figure 10B: Predicted PK and efficacy at various SC doses. Probability of meeting BICLA (in patients with high IFNGS) with weekly subcutaneous doses starting at 105 mg up to 150 mg. Assumptions for generating the data include no dose delays / interruptions. [Figure 11]C trough after thigh injection compared to abdominal injection. C trough after thigh injection tended to be lower compared to abdominal injection. Figure 11A: 150 mg SC Q2W. Figure 11B: 300 mg SC Q2W. [Figure 12] Exposure predictions based on 81-87% bioavailability and preliminary PK modeling. Predicted median Cave ratios for anifrolumab for 90-150 mg SC QW versus 300 mg Q4W based on preliminary PK modeling and bioavailability assumptions. 105 mg was initially predicted to provide a Cave comparable to 300 mg IV, assuming a bioavailability (F1) of 81-87%. [Figure 13] Cave of anifrolumab over 52 weeks in patients with high IFNGS at various SC and IV doses. When estimated bioavailability decreased below approximately 70%, the median Cave for the 105 mg QW subcutaneous dose fell to less than 1. Figure 13A: 105 mg SC QW. Figure 13B: 120 mg SC QW. Figure 13C: Overlap with 1000 mg IV Q4W. [Figure 14] Median Cave Ratio of SC QW vs. 300 mg IV Q4W. Selecting a dose above 105 mg, preferably 120 mg or greater, optimizes exposure response by minimizing the impact of variability in response onset and bioavailability in patients with lupus (e.g., SLE). Figure 14A: Estimated bioavailability of 81%. Figure 14B: Estimated bioavailability of 70%. [Figure 15] Mean Anifrolumab Concentration Versus Incidence of Shingles Incidence of Shingles (%) in Study 1013 Patients Received Placebo, 300 mg IV Anifrolumab, or 1000 mg IV Anifrolumab SC doses of less than 150 mg QW are also desirable to reduce the risk of shingles infection. [Figure 16]Schematic diagram of the PK / PD model. Nonlinear mixed-effects model. Ab: anifrolumab in the central compartment; Abp: anifrolumab in the peripheral tissue compartment; Ab.R: anifrolumab-IFNAR1 complex; CLRES: clearance by the reticuloendothelial system; GSIFN,wb: type I IFN PD signature in whole blood; IC50, potency: anifrolumab concentration corresponding to half-maximal inhibition of PD signature production; IFN: interferon; Imax: maximal fractional extent of inhibition of PD signature production by anifrolumab; kdeg,: degradation rate constant of IFN-αR1; kin,wb: production rate constant of IFN gene in whole blood; kint: internalization rate constant; koff: dissociation rate constant; kon: association rate constant; kout: elimination rate constant of IFN gene; PD: pharmacodynamics; PK: pharmacokinetics; Q: intercompartmental clearance; wb: whole blood. [Figure 17] Association between 4-gene IFNGS status (high or low) at screening and baseline 21-gene IFNGS in pooled data from the TULIP-1 and TULIP-2 trials. 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; IFNGS: interferon gene signature; SLE: systemic lupus erythematosus. Data points are shown as fold change in 21-IFNGS in patients with SLE in the TULIP-1 and TULIP-2 trials compared to 30 pooled healthy controls. Numbers shown represent the median for each group. Of the 819 patients who received at least one dose of anifrolumab 300 mg, anifrolumab 150 mg, or placebo in the TULIP-1 and TULIP-2 trials, baseline 21-IFNGS scores were missing for 25 patients (18 high-IFNGS patients and 6 low-IFNGS patients), so only 794 patients were included in this analysis. [Figure 18]IFNGS status at screening and 21-IFNGS score at baseline by age group in pooled data from TULIP-1 and TULIP-2. A negative association between age and IFNGS expression was observed for both the dichotomous IFNGS test at screening and the median 21-IFNGS score at baseline. 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; IFNGS: interferon gene signature. [Figure 19] 21-IFNGS scores (fold change relative to healthy controls) in high versus low IFNGS patients in TULIP-1 and TULIP-2. 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; IFNGS: interferon gene signature; SLE: systemic lupus erythematosus. Axes represent the median fold change in 21-IFNGS in patients with SLE relative to 30 pooled healthy controls. Error bars represent the median absolute deviation. This analysis included 439 patients in TULIP-1 and 355 patients in TULIP-2 with at least one baseline or post-baseline 21-IFNGS measurement. [Figure 20]Median 21-gene IFNGS neutralization by baseline 21-IFNGS quartile among pooled data from high-IFNGS patients treated with anifrolumab 300 mg in TULIP-1 and TULIP-2. Patients in the lowest quartile of baseline 21-IFNGS (with baseline 21-IFNGS closest to that observed in low-IFNGS patients) had more variable and lower PD neutralization than patients in higher baseline 21-IFNGS quartiles. 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; IFNGS: interferon gene signature; MAD: median absolute deviation; PD: pharmacodynamic; Q: quartile. This analysis included 291 high-IFNGS patients treated with anifrolumab 300 mg from TULIP-1 and TULIP-2 with baseline 21-IFNGS measurements. Baseline 21-IFNGS quartiles were calculated based on 794 patients (high or low IFNGS) who received at least one dose of anifrolumab 300 mg, anifrolumab 150 mg, or placebo in the TULIP-1 and TULIP-2 trials with a baseline 21-IFNGS measurement. Because this plot includes only high-IFNGS patients, there are not equal numbers in each quartile. [Figure 21] Observed PD neutralization of 21-gene type I IFNGS by Cave subgroup over the 52-week treatment period in TULIP-2 and TULIP-1. Figure 21A: TULIP-2. Figure 21A: TULIP-1. Cave: mean anifrolumab concentrations over the treatment period; IFNGS: interferon gene signature; MAD: median absolute deviation; PD: pharmacodynamics; PK: pharmacokinetics. The figure includes high IFNGS patients with ≥ 1 quantifiable serum PK observation and ≥ 1 PD measurement before discontinuation. PD measurements collected after discontinuation were not included. [Figure 22]21-IFNGS Pharmacodynamic Neutralization in High-IFNGS Patients Treated with Anifrolumab 300 mg According to Baseline Disease Characteristics: Substantial and durable PD neutralization with anifrolumab 300 mg was consistently observed across baseline disease activity subgroups, including those based on SLEDAI-2K score (<10 vs. ≥10), oral glucocorticoid dosage (<10 vs. ≥10 mg / day), and lupus serology (anti-dsDNA antibodies, C3 and C4). 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; anti-dsDNA: anti-double-stranded DNA; C3: Complement 3; C4: Complement 4; GC: glucocorticoid; IFNGS: interferon gene signature; MAD: median absolute deviation; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000. [Figure 23] Visual Predictive Check of the PK / PD Model for Anifrolumab 150 mg and 300 mg. PK / PD modeling analysis included 646 high-IFNGS patients from the pooled TULIP-1 and TULIP-2 trials who received placebo (n=289), anifrolumab 150 mg (n=70), or anifrolumab 300 mg (n=287). The PK / PD indirect response model adequately captured the observed data with a 95% prediction interval, as demonstrated by visual post-hoc predictive check. 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; Obs: observed; Obs-Med: median observed; PD: pharmacodynamics; PK: pharmacokinetics; PI: prediction interval. The dark line indicates the predicted median percent neutralization of 21-IFNGS expression. The analysis was based on 646 high IFNGS patients in the PK / PD analysis set (289 in placebo, 70 in the 150 mg group, and 287 in the 300 mg group). [Figure 24]Anifrolumab trough concentrations at week 24 predicted by the PK / PD model for anifrolumab 150 mg and 300 mg. The estimated median trough C at week 24 was higher for anifrolumab 300 mg than for anifrolumab 150 mg (15.6 vs. 0.2 μg / mL-1) due to nonlinearity. 21-IFNGS: 21-gene type I interferon gene signature; PD: pharmacodynamics; PK: pharmacokinetics. IC80 is the estimated anifrolumab concentration required to achieve 80% of maximal inhibition of 21-IFNGS expression. Predictions were based on 5000 simulations of a nonlinear mixed-effects PK / PD model implemented in the software NONMEM (version 7.3 or higher). [Figure 25] Diagnostic plots for the PK / PD model. CWRES: conditional weighted residuals; IFN: interferon; PD: pharmacodynamics; PK: pharmacokinetics. The green line represents the line of identity in Figures 25A and 25B and the LOESS (locally weighted smoothing) line in Figures 25C and 25D. [Figure 26] BICLA and SRI(4) response rates at week 52 by median quartile of type I 21-IFNGS PD neutralization in type I IFNGS-high patients. Figure 26A: BICLA; Figure 26B: SRI(4). BICLA: British Isles Lupus Assessment Group (BILAG)-based composite lupus assessment; IFNGS: interferon gene signature; PD: pharmacodynamics; SRI(4): systemic lupus erythematosus responder index ≥ 4. Analyses included IFNGS-high patients with baseline and at least one post-baseline PD assessment before discontinuation who received anifrolumab 150 mg or 300 mg (n = 341) or placebo (n = 280) in the TULIP-1 and TULIP-2 trials. PD measurements collected after discontinuation were excluded. [Figure 27]BICLA response rates for all participants based on baseline 21-IFNGS score quartiles in TULIP-1 and TULIP-2. BICLA responses were higher with anifrolumab 300 mg than with placebo across all baseline 21-IFNGS score quartiles in TULIP-1 and TULIP-2. 21-IFNGS: 21-gene pharmacodynamic interferon gene signature; BICLA: British Isles Lupus Assessment Group (BILAG)-based composite lupus assessment. Of 819 patients who received at least one dose of anifrolumab 300 mg, anifrolumab 150 mg, or placebo in TULIP-1 and TULIP-2, baseline 21-IFNGS scores were missing for 25 patients (18 with high IFNGS scores and 7 with low IFNGS scores), so only 794 patients were included in this analysis. Baseline 21-IFNGS quartiles were calculated based on the same population. [Figure 28] 21 interferon α / β-inducible genes comprising a 21-gene pharmacodynamic interferon gene signature [Figure 29] Interferon Gene Signature (IFNGS) A clear boundary exists between patients who are positive for SLE and those who are negative for the diagnostic test. Figure 29A: Fold change (RQ) signature. Figure 29B: Distribution of transcript scores for each SLE patient. The result of the test is a score that is compared to pre-established cutoffs that classify patients into two groups with low or high levels of IFN-inducible gene expression. Figure 29C: A high type I IFN gene signature is associated with high disease activity and steroid use in SLE. [Figure 30] IFNGS Neutralization Figure 30A: Study CP152 of Sifalimumab Treatment in SLE Patients Figure 30B: Changes in Type I IFNGS in Patients with High Baseline IFNGS IFNGS: Interferon Gene Signature: MAD: Median Absolute Deviation. [Figure 31]Distribution of IFNGS in type I IFN-mediated diseases. Figure 31A: Distribution of IFNGS in patients with SLE, LN, and Sjögren's syndrome. LN: lupus nephritis; SLE: systemic lupus erythematosus; HD: healthy donor. Figure 31B: Microarray analysis of whole blood and skin from patients in study MI-CP180. The IFN score is defined as the median fold change (FC) of five type I IFN-inducible genes, which were among the most differentially regulated genes in scleroderma patients compared with healthy controls. The baseline (day 0) score was used to determine whether the patient was positive or negative for the IFN signature. The five genes are a subset of the 21-gene set used to measure PD in SLE. [Figure 32] Baseline gene signature using the 5-gene IFNGS Figure 32A: Type I IFN-inducible gene signature score in whole blood (WB). Figure 32B: Type I IFN-inducible gene signature score in skin. 5-gene score: (IFI27, RSAD2, IFI44L, IFI44, IFI6). [Figure 33] Anifroluamb in SSc: Phase 1 Study Design Multicenter, open-label, dose-escalation study; 34 patients from 7 sites in the US (NCT00930683). [Figure 34]Baseline type I IFN score correlates with disease activity in scleroderma patients. Figure 34A: Comparison of the distribution of the five-gene signature between SSc and SLE at baseline. Figure 34B: IFNGS in the periphery correlates with IFNGS in diseased tissue. RNA was isolated from WB and skin at baseline, and IFN scores were determined by calculating the median fold change (FC) of five IFN-inducible genes (IFI27, IFI6, IFI44, IFI44L, and RSAD2). Correlation between peripheral and diseased tissue was assessed. Figure 34C: Baseline IFNGS correlates with disease activity score (mRTSS score). RNA was isolated from WB and skin at baseline, and IFN scores were measured. Modified Rodnan total skin score (mRTSS), an assessment of SSc disease activity, was determined by clinicians. (A) Correlation between IFN score and mRTSS in all patients is shown. (B) mRTSS scores in IFN(+) vs. IFN(-) patients reveal a significant increase in disease activity among IFN signature(+) patients. Patients were determined to be signature(+) based on cutoffs of IFN score of ≥3 on WB and ≥2 on skin. [Figure 35] Dose-dependent neutralization of (5-gene) IFN scores in WB and skin of signature-positive scleroderma patients. Patients received a single dose of anifrolumab at multiple dose levels. % neutralization was calculated relative to baseline IFN scores. [Figure 36] Therapeutic effect of anifrolumab in patients with SSc. Patients received a single dose of anifrolumab at multiple dose levels. [Figure 37] A Phase 1b Study of Sifalimumab, an Anti-IFN-α Monoclonal Antibody, in Patients with DM and PM. Protocol summary for Study MI-CP151. DM: dermatomyositis; IFN: interferon; IFNGS: interferon gene signature; IV: intravenous; PM: polymyositis; Q2W: once every 2 weeks; R: randomized. aAssessed using the Bohan and Peter 1975 criteria. bIndicates when pharmacodynamic IFNGS measurements were performed. [Figure 38] IFNGS in Myositis Patients (Study MI-CP151) We measured baseline type I IFN gene signature (13-gene score) levels in muscle and blood of DM and PM patients and found that IFNGS scores were elevated in whole blood and muscle of both BM and PM patients. [Figure 39] Neutralization of IFNGS in Myositis Patients (Study MI-CP151) Targeted modulation by sifalimumab of the type I IFN gene signature in blood or muscle of DM (Figure 39A) or PM (Figure 39A) patients from study MI-CP151. [Figure 40] Target modulation of the type I IFN gene signature in blood shows a correlative trend with disease activity in DM and PM patients (Study MI-CP151). Figure 40A: Stratified target neutralization curves depicting the proportion of DM or PM patients treated with sifalimumab who exhibit suppression of the type I IFN gene signature at day 98 at the thresholds provided on the x-axis. Patients who showed at least a 15% improvement in MMT8 score at day 98 (compared to day 0) are shown by the orange line, while those who did not are shown by the blue line. All type I IFN signature-positive patients treated with sifalimumab premedication (27). Figure 40B: Target suppression of the type I IFN gene signature correlates with suppression of key signaling events in muscle tissue. [Figure 41] Inhibition of IFNα reduces immune cell infiltration into myositic muscle (DM and PM) (study) Sifalimumab reduces immune cell infiltration in myositic muscle cells from DM and PM patients. [Figure 42] Sifalimumab improves muscle strength at pharmacologically active doses. Doses include 1 mg / kg, 3 mg / kg, and 10 mg / kg. Sifalimumab group: 14 doses (Q2W) over 6 months. Placebo group: 3 months of medication followed by a 3-month switch to sifalimumab. [Figure 43]Comparison of the IFN-Neutralizing Efficacy of Anifrolumab and Sifalimumab Both sifalimumab and anifrolumab have been tested in phase 2 clinical trials for SLE (NCT01283139 and Study 1013, respectively; Table 6-1: Clinical Studies). Both therapies had positive results, neutralizing type I IFN-GS, with the magnitude of the effect being greater for anifrolumab. [Figure 44] Delivery Device Phase 3 Study Protocol (Figure 44A). Anifrolumab will be administered via an injection device [1][9] such as a prefilled syringe (PFS) (Figure 44B) or an auto-injector (Figure 44C). [Figure 45] Auto-injector An auto-injector for administering anifrolumab in its functional variants in exploded view (FIG. 45A), assembled view (FIG. 45B) and when filled with drug substance (FIG. 45C). [Figure 46] Pre-filled syringe with accessories Pre-filled syringe with accessories (APFS) for anifrolumab and its functional variants. The main tubes are shown in assembled form (FIG. 46A) and exploded view (FIG. 46B). The APFS with additional parts is shown in assembled form (FIG. 46C) and exploded view (FIG. 46D). [Figure 47] Packaging for the delivery device [Figure 48] Anifrolumab heavy chain alignment [Figure 49] Anifrolumab light chain alignment DETAILED DESCRIPTION OF THE INVENTION

[0013] 4.1. Subcutaneous Unit Dose The present invention relates to unit doses (pharmaceutical unit doses, unit dosage forms, or pharmaceutical unit dosage forms) for subcutaneous administration comprising >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The unit doses may be packaged or formulated as unit doses (i.e., for administration to a subject in a single administration step).

[0014] The present invention relates to unit doses (pharmaceutical unit doses, unit dosage forms, or pharmaceutical unit dosage forms) for subcutaneous administration comprising >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of an IFNAR1 inhibitor. The unit doses may be packaged or formulated as unit doses (i.e., for administration to a subject in a single administration step).

[0015] A unit dose may contain ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. A unit dose may contain about 120 mg of the IFNAR1 inhibitor. A unit dose may contain 120 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of >105 mg and <150 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of ≦135 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of about 120 mg of the IFNAR1 inhibitor. The concentration of the IFNAR1 inhibitor in the unit dose may be about 150 mg / ml. The volume of the unit dose may be less than 1 ml. A dose or unit dose may have a volume of 0.5 to 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. A unit dose may comprise a formulation of 150-200 mg / ml anifrolumab or a functional variant thereof, 25-150 mM lysine salt, and an uncharged excipient. A unit dose may comprise a formulation of 150-200 mg / ml IFNAR1 inhibitor, 25-150 mM lysine salt, and an uncharged excipient. A unit dose may comprise a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05 w / v% polysorbate 80. The formulation may have a pH of about 5.9.

[0016] A unit dose may contain ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. A unit dose may contain about 120 mg of anifrolumab or a functional variant thereof. A unit dose may contain 120 mg of anifrolumab or a functional variant thereof. A unit dose may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. A unit dose may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. A unit dose may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in a unit dose may be about 150 mg / ml. The volume of a unit dose may be less than 1 ml. A dose or unit dose may have a volume of 0.5 to 1 ml. The concentration of a unit dose may be about 0.8 ml. The volume of a unit dose may be 0.8 ml. The unit dose may comprise a formulation of 150-200 mg / ml anifrolumab or functional variants thereof, 25-150 mM lysine salt, and an uncharged excipient. The unit dose may comprise a formulation of 150-200 mg / ml anifrolumab or functional variants thereof, 25-150 mM lysine salt, and an uncharged excipient. The unit dose may comprise a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05 w / v% polysorbate 80. The formulation may have a pH of about 5.9.

[0017] 4.2. Methods of Treating Type I IFN-Mediated Diseases The present invention also relates to a method for treating a type I interferon (IFN)-mediated disease in a subject, the method of treatment comprising subcutaneously administering a unit dose of the present invention to a subject having a type I interferon (IFN)-mediated disease. The present invention also relates to a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering a dose of an IFNAR1 inhibitor, the dose being greater than 105 mg and less than 150 mg. The present invention also relates to a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, the dose being greater than 105 mg and less than 150 mg.

[0018] The present invention also relates to a method for treating a type I IFN-mediated disease in a subject, comprising subcutaneously administering one dose of an IFNAR1 inhibitor, wherein administering this dose once a week provides a plasma concentration in the subject at least equivalent to that provided by intravenously administering 300 mg of an IFNAR1 inhibitor once every four weeks. Administering this dose once a week can provide a plasma concentration in the subject that exceeds that provided by intravenously administering 300 mg of an IFNAR1 inhibitor once every four weeks. Administering this dose once a week can provide a plasma concentration in the subject that is at least equivalent to that provided by intravenously administering 400 mg of an IFNAR1 inhibitor once every four weeks. This dose can be administered subcutaneously in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of the IFNAR1 inhibitor. The dose administered to the subject can be >105 mg (i.e., more than 105 mg) of the IFNAR1 inhibitor. The dose administered to a subject can be ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. The dose administered to a subject can be about 120 mg of the IFNAR1 inhibitor.

[0019] The present invention also relates to a method of treating a type I IFN-mediated disease in a subject, comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein administering the dose once weekly provides a plasma concentration in the subject at least equivalent to that provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof once every four weeks. Administering the dose once weekly can provide a plasma concentration in the subject that exceeds that provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof once every four weeks. Administering the dose once weekly can provide a plasma concentration in the subject that is at least equivalent to that provided by intravenously administering 400 mg of anifrolumab or a functional variant thereof once every four weeks. The dose can be administered subcutaneously in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be ≦135 mg (i.e., equal to or less than 135 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be about 120 mg of anifrolumab or a functional variant thereof.

[0020] The type I IFN-mediated disease can be lupus. The type I IFN-mediated disease can be systemic lupus erythematosus (SLE). Administration of a dose or unit dose can result in an improvement in the patient's BILAG-based Composite Lupus Assessment (BICLA) response rate from baseline. Administration of a dose or unit dose can result in a subject having a BICLA response, where a BICLA response is defined as: (1) at least one gradient of improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at entry (e.g., a reduction in all A (severe disease) scores to B (moderate), C (mild), or D (inactive) and a reduction in all B scores to C or D); (2) the absence of new BILAG A or two or more new BILAG B scores; (3) no worsening from baseline in all SLEDAI scores; (4) no significant worsening (≦10%) in Physician's Global Assessment; and (5) no treatment failure (initiation of non-protocol treatment). Administration of a dose or unit dose may result in an improvement from baseline in a patient's Systemic Lupus Erythematosus Responder Index (SRI) 4 score. A subject achieves SRI (4) if all of the following criteria are met: 1. A reduction from baseline of ≥ 4 points on the SLEDAI-2K; 2. No new organ systems affected as defined by ≥ 1 or ≥ 2 BILAG-2004 A; 3. BILAG-2004 B items compared to baseline using BILAG-2004; 4. No worsening from baseline in the subject's lupus disease activity as defined by an increase of ≥ 0.30 points on a 3-point PGA VAS. Lupus includes SLE, lupus nephritis, and cutaneous lupus erythematosus (CLE).

[0021] The treatment method may reduce SLE disease activity in a subject. Reducing SLE disease activity in a subject may include reducing a) the BILAG-based Composite Lupus Assessment (BICLA) response in the subject, b) the SRI(4) response in the subject, and / or the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score in the subject compared to the subject's CLASI score before treatment.

[0022] The type I IFN-mediated disease can be an autoimmune disease. The type I IFN-mediated disease can be myositis. The type I IFN-mediated disease can be Sjogren's syndrome. The type I IFN-mediated disease can be scleroderma.

[0023] Type I IFN-mediated disease can be defined as a disease in which a patient has high IFNGS compared to a healthy donor. High IFNGS can be in the patient's whole blood and / or diseased tissue (e.g., muscle and skin). High IFNGS can be measured as a 4-gene, 5-gene, or 21-gene score.

[0024] 4.3. Dosage A unit dose (also referred to as a unit dose form, pharmaceutical unit dose, or pharmaceutical unit dose form) is a dose formed from a single unit. A unit dose (unit dose form) is suitable for administration to a subject in a single administration step. A unit dose (unit dose form) can be packaged in a single unit container, such as a disposable pre-filled syringe or auto-injector. Unit doses offer the advantage that they can be ordered, packaged, handled, and administered as a single dose unit containing a predetermined amount of drug. Unit doses reduce administration errors and reduce waste.

[0025] In another aspect, the present invention relates to unit doses (pharmaceutical unit doses, unit dosage forms, or pharmaceutical unit dosage forms) for subcutaneous administration containing >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of an IFNAR inhibitor. The unit dose may contain between 105 and 149 mg of the IFNAR inhibitor.

[0026] In another aspect, the invention relates to unit doses (pharmaceutical unit doses, unit dosage forms, or pharmaceutical unit dosage forms) for subcutaneous administration comprising >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof.

[0027] A unit dose may contain ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. A unit dose may contain 105 mg to 135 mg of the IFNAR inhibitor. A unit dose may contain about 120 mg of the IFNAR1 inhibitor. A unit dose may contain 120 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of >105 mg and <150 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of ≦135 mg of the IFNAR1 inhibitor. A unit dose may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of the IFNAR1 inhibitor in the unit dose may be about 150 mg / ml. The volume of the unit dose may be 1 ml or less. A dose or unit dose may have a volume of 0.5 to 1 ml. The concentration of the unit dose may be about 0.8 ml. The volume of the unit dose may be 0.8 ml. A unit dose may include a formulation of 150-200 mg / ml of an IFNAR1 inhibitor, 25-150 mM of a lysine salt, and an uncharged excipient. A unit dose may include a formulation of 150-200 mg / ml of an IFNAR1 inhibitor, 25-150 mM of a lysine salt, and an uncharged excipient. A unit dose may include a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05 w / v% polysorbate 80. The formulation may have a pH of about 5.9.

[0028] In another aspect, the invention relates to a method for treating lupus (e.g., SLE) in a subject, the method of treatment comprising subcutaneously administering a unit dose of the invention to a subject with lupus (e.g., SLE). In another aspect, the invention also relates to a method for treating lupus (e.g., SLE) in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein the dose is >105 mg and <150 mg. In another aspect, the invention also relates to a method for treating lupus (e.g., SLE) in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein the dose is >105 mg to 149 mg.

[0029] In another aspect, the present invention also relates to a method for treating lupus (e.g., SLE) in a subject, comprising subcutaneously administering one dose of an IFNAR1 inhibitor, wherein administering this dose once weekly provides a plasma concentration in the subject at least equivalent to that provided by intravenously administering 300 mg of an IFNAR1 inhibitor once every four weeks. Administering this dose once weekly can provide a plasma concentration in the subject that exceeds that provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof once every four weeks. Administering this dose once weekly can provide a plasma concentration in the subject at least equivalent to that provided by intravenously administering 400 mg of an IFNAR1 inhibitor once every four weeks. This dose can be administered subcutaneously in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of the IFNAR1 inhibitor. The dose administered to the subject can be >105 mg (i.e., more than 105 mg) of the IFNAR1 inhibitor. The dose administered to a subject may be ≦135 mg (i.e., 135 mg or less) of the IFNAR1 inhibitor. The dose administered to a subject may be about 105 mg to 135 mg of the IFNAR1 inhibitor. The dose administered to a subject may be about 120 mg of the IFNAR1 inhibitor.

[0030] In another aspect, the present invention also relates to a method of treating lupus (e.g., SLE) in a subject, comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein administering this dose once weekly provides a plasma concentration in the subject at least equivalent to that provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof once every four weeks. Administering this dose once weekly can provide a plasma concentration in the subject that exceeds that provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof once every four weeks. Administering this dose once weekly can provide a plasma concentration in the subject that is at least equivalent to that provided by intravenously administering 400 mg of anifrolumab or a functional variant thereof once every four weeks. This dose can be administered subcutaneously in a single administration step. The dose administered to the subject can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose administered to a subject can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to a subject can be between about 105 mg and 149 mg of anifrolumab or a functional variant thereof. The dose administered to a subject can be between about 105 mg and 135 mg of anifrolumab or a functional variant thereof. The dose administered to a subject can be about 120 mg of anifrolumab or a functional variant thereof.

[0031] The methods of the present invention may include subcutaneously administering a dose or unit dose every 6 to 8 days. The dose or unit dose may be administered once per week (QW). The dose or unit dose may be 120 mg of anifrolumab or a functional variant thereof, and the method may include administering the dose in a single QW administration step. In other words, the method may include administering 120 mg of QW anifrolumab or a functional variant thereof. The dose or unit dose may be administered once per week for at least about 4 weeks. The dose or unit dose may be administered once per week for at least about 8 weeks. The dose or unit dose may be administered once per week for at least about 12 weeks. The dose or unit dose may be administered once per week for at least about 16 weeks. The dose or unit dose may be administered once per week for at least about 20 weeks. The dose or unit dose may be administered once a week for at least about 24 weeks. The dose or unit dose may be administered once a week for at least about 28 weeks. The dose or unit dose may be administered once a week for at least about 32 weeks. The dose or unit dose may be administered once a week for about 8 weeks. The dose or unit dose may have a volume suitable for delivery in a single subcutaneous administration step. The dose or unit dose may have a volume of 0.5 to 1 ml. The dose or unit dose may have a volume of less than 1 ml. The dose or unit dose may have a volume of about 0.8 ml.

[0032] Administration of a dose or unit dose may result in a patient having a plasma concentration of anifrolumab or functional variants thereof of ≥ 10 μg of anifrolumab or functional variants thereof per ml of plasma (i.e., 10 μg or more) (i.e., a plasma concentration of ≥ 10 μg / ml). Administration of a dose or unit dose may result in a subject having a plasma concentration of anifrolumab or functional variants thereof of about 10-100 μg / ml. Administration of a dose or unit dose may result in a subject having a plasma concentration of anifrolumab or functional variants thereof of 20-80 μg / ml. Administration of a dose or unit dose may result in a subject having a plasma concentration of anifrolumab or functional variants thereof of 30-70 μg / ml. Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 20 μg / ml (i.e., 20 μg / ml or more). Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 30 μg / ml (i.e., 30 μg / ml or more). Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 40 μg / ml (i.e., 40 μg / ml or more). Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of 20-100 μg / ml. Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of about 30-80 μg / ml. Administration of a dose or unit dose may result in a trough concentration of anifrolumab or a functional variant thereof in a subject of 40-70 μg / ml.

[0033] The dose or unit dose may result in a therapeutic effect in a subject that is at least equivalent to the therapeutic effect provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof administered once every four weeks (Q4W).The dose or unit dose may result in a trough concentration of anifrolumab or a functional variant thereof in a subject that is higher than the trough concentration of anifrolumab or a functional variant thereof provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof once every four weeks (Q4W).

[0034] The methods of the present invention may include subcutaneously administering a dose or unit dose every 6 to 8 days. The dose or unit dose may be administered once per week (QW). The dose or unit dose may be 120 mg of anifrolumab or a functional variant thereof, and the method may include administering the dose in a single QW administration step. In other words, the method may include administering 120 mg of QW anifrolumab or a functional variant thereof. The dose or unit dose may be administered once per week for at least 4 weeks. The dose or unit dose may be administered once per week for at least 8 weeks. The dose or unit dose may be administered once per week for at least 12 weeks. The dose or unit dose may be administered once per week for at least 16 weeks. The dose or unit dose may be administered once per week for at least 20 weeks. The dose or unit dose may be administered once per week for at least 24 weeks. The dose or unit dose may be administered once a week for at least 28 weeks. The dose or unit dose may be administered once a week for at least 32 weeks. The dose or unit dose may be administered once a week for approximately 8 weeks. The dose or unit dose may have a volume suitable for delivery in a single subcutaneous administration step. The dose or unit dose may have a volume of 0.5 to 1 ml. The dose or unit dose may have a volume of less than 1 ml. The dose or unit dose may have a volume of approximately 0.8 ml.

[0035] Administration of a dose or unit dose may result in a patient having a plasma concentration of anifrolumab or functional variants thereof of ≥ 10 μg of anifrolumab or functional variants thereof per ml of plasma (i.e., 10 μg or greater). Administration of a dose or unit dose may result in a subject having a plasma concentration of anifrolumab or functional variants thereof of 10-100 μg / ml. Administration of a dose or unit dose may result in a subject having a plasma concentration of anifrolumab or functional variants thereof of 20-80 μg / ml. Administration of a dose or unit dose may result in a subject having a plasma concentration of anifrolumab or functional variants thereof of 30-70 μg / ml. Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 20 μg / ml (i.e., 20 μg / ml or more). Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 30 μg / ml (i.e., 30 μg / ml or more). Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 40 μg / ml (i.e., 40 μg / ml or more). Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of 20-100 μg / ml. Administration of a dose or unit dose may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of about 30-80 μg / ml. Administration of a dose or unit dose may result in a trough concentration of anifrolumab or a functional variant thereof in a subject of 40-70 μg / ml.

[0036] The dose or unit dose may result in a therapeutic effect in a subject that is at least equivalent to the therapeutic effect provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof administered once every four weeks (Q4W).The dose or unit dose may result in a trough concentration of anifrolumab or a functional variant thereof in a subject that is higher than the trough concentration of anifrolumab or a functional variant thereof provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof once every four weeks (Q4W).

[0037] The dose or unit dose can be 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg or 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, or 149 mg.

[0038] 4.4. Subject The subject may be a human subject. The subject may be an adult. The subject may have lupus. The subject may have SLE. The subject may have active SLE. The subject may have moderate to severe SLE. The subject may have lupus nephritis (LN). The subject may have CLE. The subject may have myositis. The subject may have scleroderma. The subject may have Sjogren's syndrome.

[0039] The subject may be a patient with a high type I IFN gene signature. The subject may be a patient with a high type I interferon-stimulated gene signature (IFNGS) test result prior to administration of the dose or unit dose. The IFNGS may be a 21-gene signature. The IFNGS may be a 4-gene signature. The IFNGS may be a 5-gene signature. The subject may have high expression levels of the genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. The subject may have high expression levels of the genes IFI27, RSAD2, IFI44, IFI44L, and IFI6 in whole blood. The method may include identifying the subject as a patient with a high IFNGS test result prior to treatment with the dose or unit dose. The method may include measuring expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subject's whole blood. The method may include measuring the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subject. The method may include measuring the expression of genes IFI27, RSAD2, IFI44, IFI44L, IFI6 in the whole blood of the subject by RT-PCR. Gene expression may be measured in a sample isolated from the subject. The measurement may include a physical measurement step.

[0040] The subject may have, at baseline (i.e., before treatment with the dose), a 21-IFNGS score of about 13. The subject may have, at baseline (i.e., before treatment with the dose), a 21-IFNGS score of about 10, 11, 12, 13, 14, 15, or 16. The subject may have, at baseline (i.e., before treatment with the dose), a 21-IFNGS score of about 13.1.

[0041] Pharmaceutical Compositions In another aspect, the present invention relates to a pharmaceutical composition for use in treating SLE in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, the pharmaceutical composition comprising a unit dose of the present invention.

[0042] In another aspect, the present invention relates to a pharmaceutical composition for use in a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising a unit dose of the present invention.

[0043] In another aspect, the present invention relates to a pharmaceutical composition for use in a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of anifrolumab or a functional variant thereof, the dose being greater than 105 mg and less than 150 mg. The dose of anifrolumab or a functional variant thereof can be a unit dose (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab, as well as antibodies and immunoglobulin derivatives of anifrolumab.

[0044] In another aspect, the present invention relates to a pharmaceutical composition for use in a method for treating a type I IFN-mediated disease in a subject, the method comprising subcutaneously administering the pharmaceutical composition to the subject, the pharmaceutical composition comprising a dose of anifrolumab or a functional variant thereof, wherein weekly administration of the pharmaceutical composition provides a plasma concentration in the subject at least equivalent to that provided by intravenous administration of 300 mg of anifrolumab or a functional variant thereof once every four weeks. Weekly administration of this dose can provide a plasma concentration in the subject approximately equivalent to that provided by intravenous administration of 400 mg of anifrolumab or a functional variant thereof once every four weeks. The dose can be <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose can be >105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose can be ≦135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose can be about 120 mg of anifrolumab or a functional variant thereof. The dose can be 120 mg of anifrolumab or a functional variant thereof.

[0045] Administration of the pharmaceutical composition may result in a patient having a plasma concentration of anifrolumab or a functional variant thereof of ≥ 10 μg of anifrolumab or a functional variant thereof per ml of plasma (i.e., 10 μg or more). Administration of the pharmaceutical composition may result in a subject having a plasma concentration of anifrolumab or a functional variant thereof of 10-100 μg / ml. Administration of the pharmaceutical composition may result in a subject having a plasma concentration of anifrolumab or a functional variant thereof of 20-80 μg / ml. Administration of the pharmaceutical composition may result in a subject having a plasma concentration of anifrolumab or a functional variant thereof of 30-70 μg / ml. Administration of the pharmaceutical composition may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 20 μg / ml (i.e., 20 μg / ml or more). Administration of the pharmaceutical composition may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 30 μg / ml (i.e., 30 μg / ml or more). Administration of the pharmaceutical composition may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of ≥ 40 μg / ml (i.e., 40 μg / ml or more). Administration of the pharmaceutical composition may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of 20-100 μg / ml. Administration of the pharmaceutical composition may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of 30-80 μg / ml. Administration of the pharmaceutical composition may result in a subject having a trough concentration of anifrolumab or a functional variant thereof of 40-70 μg / ml.

[0046] The pharmaceutical composition may provide a therapeutic effect in a subject at least equivalent to that provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof administered once every four weeks (Q4W). The pharmaceutical composition may provide a trough concentration of anifrolumab or a functional variant thereof in a subject that is greater than the trough concentration of anifrolumab or a functional variant thereof provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof once every four weeks (Q4W). Anifrolumab or a functional variant thereof may be contained within a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0047] 4.6. Formulation The IFNAR1 inhibitor may be contained in a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / mL of the IFNAR1 inhibitor, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may comprise 150 mg / mL of the IFNAR1 inhibitor, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0048] Anifrolumab or a functional variant thereof may be contained within a pharmaceutical composition. The pharmaceutical composition may comprise about 150-200 mg / ml of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM lysine HCl. The pharmaceutical composition may comprise 130 mM trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition may include 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0049] A unit dose may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. A unit dose may comprise 150 mg / mL of anifrolumab or a functional variant thereof. A unit dose may comprise 50 mM of lysine HCl. A unit dose may comprise 130 mM of trehalose dihydrate. A unit dose may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. A unit dose may comprise 150 mg / mL of anifrolumab or a functional variant thereof. A unit dose may comprise 50 mM of lysine HCl. A unit dose may comprise 130 mM of trehalose dihydrate. The unit dose may include 0.05% polysorbate 80. The unit dose may include 25 mM histidine / histidine HCl. The unit dose may include 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0050] The pharmaceutical composition may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition may comprise about 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition may comprise 0.05% polysorbate 80. The pharmaceutical composition may include 25 mM histidine / histidine HCl. The pharmaceutical composition may include 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0051] Stable formulations containing anifrolumab suitable for administration to a subject are described in detail in U.S. Pat. No. 10,125,195 B1, which is incorporated herein in its entirety.

[0052] Steroids Many patients with lupus (e.g., SLE) are administered corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows for the tapering of corticosteroids (glucocorticoids) (reduced steroid use) in patients with lupus (e.g., SLE). A treatment method or method can include administering a corticosteroid to a subject, optionally where the corticosteroid is an oral corticosteroid. The method can include tapering the dose of corticosteroid administered to the subject (reduced steroid use). The method can include administering an initial dose of corticosteroid followed by a second dose of corticosteroid, where the second dose of corticosteroid is less than the initial dose of corticosteroid. The second dose of corticosteroid can be equal to or less than about 7.5 mg prednisone equivalent (see Table 5-4). The second dose of corticosteroid can be a 5 mg prednisone equivalent dose or less. The method or treatment method can include administering the second dose of corticosteroid once daily. The initial dose of corticosteroid can be about a 10 mg prednisone equivalent dose. The method can include tapering the dose of corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or treatment method can include administering the second dose of corticosteroid once per day. The method can allow for administration of a reduced dose of corticosteroid lasting for several weeks. The second dose of corticosteroid can be administered for at least 24 weeks. The second dose of corticosteroid can be administered for at least 28 weeks.

[0053] The methods of the present invention may include administering standard of care (SOC) to a subject. The methods of the present invention may include administering a steroid to a subject. The methods or methods of the present invention may include reducing steroid use in a subject, wherein the steroid dose administered to the subject is tapered from a pre-reduction dose at baseline to a post-reduction dose.

[0054] The method can include reducing steroid use in a subject, wherein the steroid dose administered to the subject is tapered from a pre-reduction dose at baseline to a post-reduction dose. The post-reduction dose can be a dose of ≦7.5 mg / day of prednisone or prednisone equivalent. The pre-reduction dose can be a dose of 20 mg / day of prednisone or prednisone equivalent. The steroid can include a glucocorticoid. The steroid can include an oral glucocorticoid. Steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, and flucortolone. , fluprednidene, fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or a mixture thereof. The steroid can be prednisone.

[0055] 4.8. Equipment The present invention also relates to an injection device comprising a unit dose of the present invention or a pharmaceutical composition for any use of the present invention. The medicament in the injection device may contain >105 mg (i.e., more than 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may contain about 120 mg of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may contain 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the pharmaceutical composition in the injection device may be 150 mg / ml. The volume of the pharmaceutical composition in the injection device may be at least about 0.8 ml. The volume of the pharmaceutical composition may be about 0.8 ml.

[0056] The pharmaceutical composition in the injection device may comprise approximately 150-200 mg / mL of anifrolumab or a functional variant thereof, 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition in the injection device may comprise 50 mM of lysine HCl. The pharmaceutical composition may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise approximately 150-200 mg / mL of anifrolumab or a functional variant thereof, about 25-150 mM of a lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may comprise 150 mg / mL of anifrolumab or a functional variant thereof. The pharmaceutical composition may comprise 50 mM of lysine HCl. The pharmaceutical composition in the injection device may comprise 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may comprise 0.05% polysorbate 80. The pharmaceutical composition in the injection device may comprise 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0057] In addition to providing subcutaneous administration of antibodies, the ability to self-administer (e.g., for home use) can be further enhanced by subcutaneous administration via an accessory prefilled syringe (APFS), an autoinjector (AI), or a combination thereof. Such devices have been found to be well tolerated and reliable for administering subcutaneous doses of antibodies, providing additional options for optimizing patient care. Naturally, such devices may reduce the burden of frequent clinic visits for patients. An example of a suitable APFS device is described in Ferguson et al. [6], which is incorporated herein by reference in its entirety.

[0058] Because APFS devices typically administer a maximum volume of 1 ml, the doses discovered by the inventors offer additional advantages for the administration of APFS. Because doses in the range of >105 mg to <155 mg can be easily accommodated in a volume of approximately 0.8 ml, the doses of the present invention are uniquely suited for the administration of APFS and AIs. For comparison, due to the viscosity of anifrolumab, larger doses (e.g., doses >150 mg) must be administered in a volume >1 ml, which requires at least two SC injections, which is inconvenient for patients and requires multiple prefilled devices.

[0059] The delivery device can be a single-use, disposable system designed to allow manual SC administration of this dose.

[0060] The present invention also relates to an injection device comprising a unit dose. The unit dose may contain >105 mg (i.e., at least 105 mg) and <150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The unit dose may contain ≦135 mg (i.e., ≦135 mg) of anifrolumab or a functional variant thereof. The unit dose may contain about 120 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may contain 120 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may consist essentially of >105 mg and <150 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may consist essentially of ≦135 mg of anifrolumab or a functional variant thereof. The unit dose of the injection device may consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or functional variants thereof in a unit dose in the injection device may be about 150 mg / ml. The volume of a unit dose in the injection device may be less than 1 ml. The unit dose in the injection device may have a volume of 0.5 to 1 ml. The concentration of a unit dose may be about 0.8 ml. The volume of a unit dose may be 0.8 ml. A unit dose in the injection device may comprise a formulation of about 150 to 200 mg / ml of anifrolumab or functional variants thereof, about 25 to 150 mM of a lysine salt, and an uncharged excipient. A unit dose in the injection device may comprise a formulation of 150 to 200 mg / ml of anifrolumab or functional variants thereof, 25 to 150 mM of a lysine salt, and an uncharged excipient. The unit dose comprises a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of about 5.9.

[0061] The injection device may be a pre-filled syringe (PFS). The injection device may be a pre-filled syringe with accessory (AFPS). The injection device may be an automatic injector (AI).

[0062] 4.9.Kit The invention also relates to a kit comprising a unit dose of the invention and instructions for use, wherein the instructions for use include instructions for subcutaneously administering the unit dose to a subject.The invention also relates to a kit comprising a pharmaceutical composition for use of the invention, wherein the instructions for use include instructions for subcutaneously administering the pharmaceutical composition to a subject.

[0063] The present invention also relates to a kit comprising any of the injection devices of the present invention and instructions for use, wherein the instructions for use include instructions for use of the injection device for subcutaneously administering a unit dose or pharmaceutical composition to a subject.

[0064] The instructions may specify that the injection device, unit dose, and / or pharmaceutical composition is for use in treating SLE. The kits of the invention may include packaging configured to hold the injection device and instructions. The instructions may be attached to the injection device. The instructions may include instructions for administering >105 mg and <150 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering ≦135 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 120 mg of anifrolumab or a functional variant thereof. The instructions may include instructions for administering 120 mg of anifrolumab or a functional variant thereof once every four weeks. The instructions may define the subject as having a type I IFN-mediated disease. The instructions may define the subject as having lupus (e.g., SLE). The instructions may be written instructions. The instructions may specify that the type I IFN inhibitor is for subcutaneous administration.

[0065] The instructions for use may specify that the injection device, unit dose, and / or pharmaceutical composition is for use in any of the methods of the invention.

[0066] The present invention also relates to a method for producing a kit of the invention, or a pharmaceutical composition of the invention, or a unit dose of the invention.

[0067] 4.10. Inhibitors of Type I IFN-Mediated Signaling The inhibitor of type I IFN-mediated signal transduction can be an IFNAR1 inhibitor. The IFNAR1 inhibitor can be a human monoclonal antibody specific to IFNAR1. The IFNAR1 inhibitor can be a modified IgG1 class human monoclonal antibody specific to IFNAR1.

[0068] The antibody may comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3. The antibody may comprise a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4. The antibody may comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5. The antibody may comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6. The antibody may comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7. The antibody may comprise a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0069] The antibody may comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1. The antibody may comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The antibody may comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9. The antibody may comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The antibody may comprise an amino acid substitution of L234F, as numbered by the EU index as set forth in Kabat, in the Fc region, wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. The antibody may comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11. The antibody may comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0070] The antibody may comprise: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; (c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (b) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and (c) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0071] The antibody may comprise (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO:11, and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:12.

[0072] The IFNAR1 inhibitor can be anifrolumab or a functional variant thereof.

[0073] The IFNAR1 inhibitor is approximately 3.88 μg mL -1 IC 80 where IC 80 is defined as the approximate concentration required to obtain a maximal inhibition of 21-IFNGS expression of 80% compared to baseline. IFNAR1 inhibitors have an IC of approximately 6. 50 The IFNAR1 inhibitor may have an IC of about 6.56 nM. 50 may have:

[0074] 5.Definition 5.1. Inhibitors of type I IFN signaling Anifrolumab Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and suppresses IFN-inducible gene expression. Disclosures regarding anifrolumab can be found in U.S. Pat. Nos. 7,662,381 and 9,988,459, which are incorporated by reference in their entireties. Sequence information for anifrolumab is shown in Table 5-1, and the sequences are shown in Figures 48 and 49.

[0075] [Table 1]

[0076] Anifrolumab is a human immunoglobulin G1 kappa monoclonal antibody that binds with high specificity and affinity to subunit 1 of the type I interferon receptor (IFNAR1). This binding inhibits type I IFN signaling, thereby blocking the biological activity of type I IFN. Anifrolumab also induces IFNAR1 internalization, thereby reducing the level of cell surface IFNAR1 available for receptor assembly. Blocking receptor-mediated type I IFN signaling inhibits IFN-responsive gene expression and downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation, normalizes peripheral T cell subsets, and restores the balance between adaptive and innate immunity, which is dysregulated in SLE.

[0077] In adult patients with SLE, anifrolumab administered at doses ≥300 mg by intravenous infusion once every 4 weeks demonstrated uniform neutralization (≥80%) of the 21-gene type I interferon pharmacodynamic (PD) signature in the blood. This suppression occurred as early as 4 weeks after treatment and was maintained or further suppressed over the 52-week treatment period. After discontinuation of anifrolumab at the end of the 52-week treatment period in an SLE clinical trial, the type I IFN PD signature in blood samples returned to baseline levels within 8 to 12 weeks. Anifrolumab 150 mg IV demonstrated <20% suppression of the gene signature at early time points, which reached a maximum of <60% by the end of the treatment period.

[0078] Anifrolumab is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, respectively; and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, respectively. Anifrolumab is an immunoglobulin comprising a VH of SEQ ID NO:1 and a VL of SEQ ID NO:2.

[0079] The constant region of anifrolumab has been modified so that anifrolumab exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1, containing an L234F amino acid substitution in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1, containing an L234F, L235E, and / or P331S amino acid substitution in the Fc region, as numbered by the EU index as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO:9. Anifrolumab is an antibody comprising a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody comprising a light chain of SEQ ID NO: 12. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0080] A functional variant of anifrolumab is a sequence variant that performs the same function as anifrolumab. A functional variant of anifrolumab is a variant that binds to the same target as anifrolumab and has the same effector function as anifrolumab. Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibodies and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable products are defined by the FDA and EMA. The term biosimilar refers to a biological product that is highly similar in structure to an approved (e.g., FDA-approved) biological product (reference product, e.g., anifrolumab) and does not have clinically significant differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically significant differences of a biosimilar may be evaluated in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and clinical immunogenicity evaluations. An interchangeable product is a biosimilar that is expected to produce the same clinical outcome as the reference product in any given patient.

[0081] For example, a variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 with up to two amino acid differences compared to SEQ ID NO:3; a heavy chain CDR2 with up to two amino acid differences compared to SEQ ID NO:4; a heavy chain CDR3 with up to two amino acid differences compared to SEQ ID NO:5; a light chain CDR1 with up to two amino acid differences compared to SEQ ID NO:6; a light chain CDR2 with up to two amino acid differences compared to SEQ ID NO:7; and a light chain CDR3 with up to two amino acid differences compared to SEQ ID NO:8, wherein the variant antibody binds to the target of anifrolumab (e.g., IFNAR), preferably with the same affinity.

[0082] A variant of a reference (anifrolumab) antibody may comprise a heavy chain CDR1 with at most one amino acid difference compared to SEQ ID NO:3; a heavy chain CDR2 with at most one amino acid difference compared to SEQ ID NO:4; a heavy chain CDR3 with at most one amino acid difference compared to SEQ ID NO:5; a light chain CDR1 with at most one amino acid difference compared to SEQ ID NO:6; a light chain CDR2 with at most one amino acid difference compared to SEQ ID NO:7; and a light chain CDR3 with at most one amino acid difference compared to SEQ ID NO:8, wherein the variant antibody binds to the target of anifrolumab (e.g., IFNAR), optionally with the same affinity.

[0083] A variant antibody may have up to 5, 4 or 3 amino acid differences overall in its CDRs when compared to a corresponding reference (anifrolumab) antibody, provided that there are up to two (optionally, up to one) amino acid differences per CDR. A variant antibody may have up to two (optionally, up to one) amino acid differences overall in its CDRs when compared to a corresponding reference (anifrolumab) antibody, provided that there are up to two amino acid differences per CDR. A variant antibody may have up to two (optionally, up to one) amino acid differences overall in its CDRs when compared to a corresponding reference (anifrolumab) antibody, provided that there is up to one amino acid difference per CDR.

[0084] A variant antibody may have at most 5, 4, or 3 amino acid differences overall in its framework regions when compared to a corresponding reference (anifrolumab) antibody, provided that there are at most two (optionally, at most one) amino acid differences per framework region. Optionally, a variant antibody has at most two (optionally, at most one) amino acid differences overall in its framework regions when compared to a corresponding reference (anifrolumab) antibody, provided that there are at most two amino acid differences per framework region. Optionally, a variant antibody has at most two (optionally, at most one) amino acid differences overall in its framework regions when compared to a corresponding reference (anifrolumab) antibody, provided that there is at most one amino acid difference per framework region.

[0085] The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has up to 14 amino acid differences (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region) compared to the heavy chain sequences herein, and the light chain has up to 14 amino acid differences (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region) compared to the light chain sequences herein, and wherein the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0086] A variant heavy or light chain may be referred to as a "functional equivalent" of a reference heavy or light chain. The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has up to seven amino acid differences (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region) compared to the heavy chain sequences herein, and the light chain has up to seven amino acid differences (up to one amino acid difference in each CDR and up to one amino acid difference in each framework region) compared to the light chain sequences herein, and the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anifrolumab) antibody, preferably with the same affinity.

[0087] Functional variants of anifrolumab include the antibodies described in WO 2018 / 023976 A1, which is incorporated herein by reference (Table 5-2).

[0088] [Table 2]

[0089] Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0090] The IFNAR inhibitor may be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 13. The anti-IFNAR antibody may comprise the VH amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 14. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody may comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0091] Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in Chinese Patent No. 11327807, which is incorporated herein by reference.

[0092] [Table 3]

[0093] The IFNAR inhibitor can be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody can comprise the VL amino acid sequence of SEQ ID NO: 18.

[0094] QX006N is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively, and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 23, respectively. QX006N is an immunoglobulin comprising a VH amino acid sequence of SEQ ID NO: 17 and a VL amino acid sequence of SEQ ID NO: 18.

[0095] Sifalimumab Sifalimumab (MEDI-545) is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes [7]. Sifalimumab is described in U.S. Patent No. 7,741,449, which is incorporated herein by reference in its entirety. The efficacy and safety of sifalimumab were evaluated in a Phase IIb, randomized, double-blind, placebo-controlled study (NCT01283139) in adults with moderately to severely active systemic lupus erythematosus (SLE). 431 patients were randomized to receive monthly intravenous sifalimumab (200 mg, 600 mg, or 1200 mg) or placebo in addition to standard of care. The primary efficacy endpoint was the proportion of patients achieving an SLE responder index response at week 52. Compared with placebo, a greater proportion of patients receiving sifalimumab (all dosages) met the primary endpoint (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg: 59.8%).

[0096] Steroids Oral corticosteroids (OCS, glucocorticoids) include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone, and triamcinolone. Examples of equivalent doses of oral prednisone are shown in (Table 5-4).

[0097] [Table 4]

[0098] 5.3.Evaluation Items 5.3.1. Systemic Lupus Erythematosus Responder Index (SRI) ≥ 4 A subject achieves SRI(4) if all of the following criteria are met: · ≥ 4-point reduction from baseline in SLEDAI-2K; No new affected organ systems as defined by 1 or 2 BILAG-2004 A · BILAG-2004 B items will be compared with baseline using BILAG-2004; · No worsening from baseline in the subject's lupus disease activity, as defined by an increase of ≥ 0.30 points on the 3-point PGA VAS.

[0099] SRI(X) (X=5, 6, 7, or 8) is defined by the proportion of subjects meeting the following criteria: · A decrease from baseline of ≥ X points in SLEDAI-2K; No new affected organ systems as defined by 1 or 2 BILAG-2004 A, or More BILAG-2004 B items will be compared with baseline using BILAG-2004; A 3-point PGA VAS, as defined by a ≥ 0.30-point increase No worsening of the subject's lupus disease activity from baseline

[0100] 5.3.2. SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) The SLEDAI-2K Disease Activity Index consists of a list of organ signs, each with a definition. A certified investigator or designated physician will complete the SLEDAI-2K assessment and determine whether each sign is "present" or "absent" within the last four weeks. The assessment also includes blood and urine collection for evaluation of the laboratory categories of the SLEDAI-2K.

[0101] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighting system, in which descriptors are multiplied by the "weight" of a specific organ. For example, the renal descriptor is multiplied by 4, the central nervous system descriptor is multiplied by 8, and these weighted organ manifestations are summed to form a final score. The SLEDAI-2K score ranges from 0 to 105 points, with 0 indicating inactive disease. The SLEDAI-2K score is a valid, reliable, and sensitive clinical assessment of lupus disease activity.

[0102] BILAG-2004 (British Isles Lupus Assessment Group-2004) The BILAG-2004 is a translational index across nine organ systems (systemic, mucocutaneous, neuropsychiatric, musculoskeletal, cardiopulmonary, gastrointestinal, ocular, renal, and hematologic) that can capture the change in severity of clinical signs in SLE patients. It has an ordinal scale by design and does not have a total score; rather, it records disease activity across different organ systems at a glance by comparing the last four weeks with the four weeks preceding them. It classifies disease activity into five different levels, A through E, based on the physician's intention-to-treat principle: Grade A represents very active disease requiring immunosuppressants and / or prednisone or equivalent in doses >20 mg / day Grade B represents moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressants, antimalarials, or NSAIDs Grade C refers to mild stable disease Grade D means there is no disease activity, but the system has been previously affected Grade E indicates no current or previous disease activity

[0103] Although BILAG-2004 was developed on the intention-to-treat principle, treatment has no bearing on the scoring index. Only the presence of active symptoms influences the scoring.

[0104] 5.3.4. BICLA (BILAG-based Composite Lupus Assessment) BICLA is a composite index originally derived by expert consensus on disease activity index. BICLA response is defined as (1) at least one gradient of improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at entry (e.g., a reduction in all A (severe disease) scores to B (moderate), C (mild), or D (inactive) and a reduction in all B scores to C or D); (2) the absence of new BILAG A or two or more new BILAG B scores; (3) no worsening from baseline in all SLEDAI scores; (4) no significant worsening (≦10%) in Physician's Global Assessment; and (5) no treatment failure (initiation of non-protocol treatment).

[0105] In particular, a subject is a BICLA responder if the following criteria are met: · Reduction of all baseline BILAG-2004A to B / C / D, reduction of baseline BILAG-2004B to C / D, and no worsening of BILAG-2004 in other organ systems, as defined by one new BILAG-2004A or two or more new BILAG-2004B items; ·No worsening from baseline on the SLEDAI-2K, defined as an increase from baseline of >0 points on the SLEDAI-2K; ·No worsening from baseline in the subject's lupus disease activity, defined by an increase of ≥ 0.30 points on a 3-point PGA VAS;

[0106] BICLA response is a composite endpoint requiring improvement in all baseline BILAG-2004A and B scores, no worsening as assessed by SLEDAI-2K and PGA, and no discontinuation of IP and no use of prohibited substances above protocol-accepted thresholds. BILAG captures relative improvement in organ systems (in contrast to SLEDAI-2K, which is used to indicate improvement in SRI and requires complete resolution in an organ system); BILAG-2004, used to measure improvement in BICLA, can detect clinically significant relative improvement in organ systems.

[0107] 5.3.5. CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) The CLASI is a proven index used to evaluate skin lesions in SLE and consists of two separate scores: the first summarizes the inflammatory activity of the disease; the second is a measure of the damage caused by the disease. The activity score takes into account erythema, scaling / thickening, mucosal lesions, recent hair loss, and non-scarring alopecia. The damage score represents pigmentation abnormalities, scarring / atrophy / panniculitis, and scalp scarring. Subjects are asked whether their pigmentation abnormalities have persisted for more than 12 months; if so, a pigmentation abnormality score is suspected. Each of the above parameters is measured at 13 different anatomical locations and specifically included because they are most commonly involved in cutaneous lupus erythematosus (CLE). The most severe lesions within each area are measured.

[0108] 5.3.6. Tender and swollen joints Swollen and tender joint counts may be based on the left and right shoulders, elbows, wrists, metacarpophalangeal (MCP) 1, MCP2, MCP3, MCP4, and MCP5 joints, proximal interphalangeal (PIP) 1, PIP2, PIP3, PIP4, and PIP5 joints of the upper limbs, and the left and right knees of the lower limbs. Active joints for joint count assessment may be defined as those joints that are tender and swollen.

[0109] 5.4. Pharmacokinetic Terminology Area Under the Curve (AUC): The area under the plasma drug concentration versus time curve, which serves as an index of drug exposure.

[0110] C ave : Steady-state average concentration.

[0111] C max : The maximum (or peak) concentration of a drug in plasma.

[0112] C min :Minimum plasma drug concentration.

[0113] C トラフ : The steady-state plasma drug concentration immediately prior to administering the next dose. Trough plasma concentration (the concentration measured at the end of the dosing interval at steady state (taken immediately prior to the next dose)).

[0114] LLOQ: Lower Limit of Quantitation (the lowest amount of analyte in a sample that can be quantitatively determined with suitable precision and accuracy).

[0115] Linear pharmacokinetics: Drugs are said to exhibit linear pharmacokinetics if their blood or plasma concentration increases proportionally with increasing dose and their rate of elimination is proportional to concentration. The clearance and volume of distribution of these drugs are dose-dependent.

[0116] Nonlinear pharmacokinetics: Contrary to linear pharmacokinetics, drug concentrations in blood or plasma do not increase proportionally with increasing dose. Their clearance and volume of distribution may vary depending on the administered dose. Nonlinearity may be associated with any component of the absorption, distribution, and / or elimination processes.

[0117] 5.5.PK / PD The plasma levels obtainable by SC and IV administration can be compared based on the plasma drug concentration-time curve (AUC), which reflects the body's exposure to the antibody after administration of a certain dose of drug. For example, during a clinical study, a patient's plasma drug concentration-time profile can be plotted by measuring plasma concentrations at several time points. If a computer modeling approach is used, the plasma drug concentration-time for any given dose can be predicted. The AUC (area under the curve) can then be calculated by integrating the plasma drug concentration-time curve. A suitable methodology is described in Tummala et al. [8], which is incorporated herein by reference in its entirety. In the examples described herein, PK parameters were calculated by noncompartmental analysis using Phoenix WinNonlin V / 6.2 (Certara, Inc., Princeton, New Jersey, USA), and included the serum concentration-time curve (AUC), clearance (CL, CL / F), and maximum serum concentration (C). max ), and time to reach maximum serum concentration (t max All data were analyzed using SAS System V.9.2 (SAS Institute, Inc., Cary, NC, USA).

[0118] Advantageously, the ratio of AUC obtainable by IV administration to AUC obtainable by SC administration (AUC SC / AUC IV ) can be calculated to provide a numerical comparison of the bioavailability provided by the routes of administration. As used herein, references to "AUC ratio" refer to the AUC SC / AUC IVThe AUC ratio means a ratio. To provide statistical robustness, the AUC ratio is preferably the mean, median, or mode (e.g., average) value calculated from multiple repeated experiments (or computer simulations). This approach is demonstrated with reference to the Examples. The mean, median, or mode (preferably average) can be derived by pooling data obtained from multiple patients (or multiple computer simulations). Thus, the AUC ratio can reflect the mean, median, or mode (preferably average) AUC in multiple patients.

[0119] Nonlinear PK occurs when clearance is not constant, or in other words, when clearance varies with dose.

[0120] 5.6.Type I IFN-mediated diseases Type I IFN-mediated diseases can be defined as diseases characterized by dysregulation of type I IFN [9]. Type I IFN diseases can be type I IFN-mediated autoimmune diseases. Type I IFN diseases can be type I IFN-mediated systemic autoimmune diseases. Type I IFN-mediated diseases include lupus (including SLE, LN, and CLE). Type I IFN-mediated diseases can be lupus nephritis. Type I IFN-mediated diseases include cutaneous lupus erythematosus. Type I IFN-mediated diseases include myositis. Type I IFN-mediated diseases include scleroderma. Type I IFN-mediated diseases include Sjögren's syndrome.

[0121] Type I IFN-mediated diseases include interferonopathy.Type I IFN-mediated diseases can be characterized by a high association with 21 genes IFNGS compared to healthy subjects.Type I IFN-mediated diseases can be characterized by a high association with 4 genes IFNGS compared to healthy subjects.Type I IFN-mediated diseases can be characterized by a high association with 5 genes IFNGS compared to healthy subjects.

[0122] Myositis Myositis, including SLE (also known as idiopathic inflammatory myopathy (IMM)), is a connective tissue disorder strongly associated with type 1 IFN. Myositis is a rare, progressive, and debilitating disease. It is a type I IFN-mediated disorder. Specifically, type I IFN-inducible genes are overexpressed in the whole blood and muscle of patients with myositis [10, 11]. Type I IFN gene expression correlates with myositis disease activity [10, 11]. Furthermore, type I IFN-secreting plasmacytoid DCs (pDCs) are present in target tissues of patients with myositis [12, 13]. In addition, myositis can be newly induced or exacerbated by IFN treatment [13, 14]. Finally, the anti-IFN-α monoclonal antibody sifalimumab neutralized IFN gene expression in both DM and PM muscle, which was associated with improved muscle function (see Examples, Section 11.4). Clinical signs of fatigue, rash, photosensitivity, and joint pain are common to both lupus and myositis.

[0123] Scleroderma Systemic sclerosis (SSc), including SLE, is a connective tissue disorder in which type 1 IFN is strongly involved. Systemic sclerosis is a multisystem autoimmune disease characterized by functional and structural abnormalities of the microvasculature and fibrosis of the skin and visceral organs. The type 1 IFN pathway is a pathogenic driver in SSc. Evidence for the central role of type 1 IFN in the pathogenesis of SSc (inflammatory and fibrotic processes) includes multiple associated genetic polymorphisms involving the type 1 IFN pathway in SSc

[15] . Furthermore, autoantibodies in SSc have been shown to directly amplify type 1 IFN responses

[16] , and there is evidence that type 1 IFN contributes to TGF-β-dependent and -independent fibrosis in the lungs and skin of SSc patients

[17] . Additionally, digital ulcers resulting from small-vessel vascular lesions in SSc are associated with a high IFN signature

[18] .

[0124] 5.7. Type I IFN Gene Signature (IFNGS) The interferon gene signature (IFNGS) is defined as a set of specific gene transcripts whose expression increases upon activation of the IFN receptor (IFNAR1) by binding of type I IFN ligands (IFN-α, IFN-β, and IFN-ω). To provide distinct measurements, two interferon gene signatures are used as part of the Saphnelo and sifalimumab studies: the 4-gene interferon gene signature is a peripheral blood signature derived from a genome-wide gene expression study and further validated by a quantitative PCT study (developed to specifically measure IFN gene expression based on four genes). This is further used to understand whether a disease or a particular patient's disease is type I IFN-driven at baseline. The 21-interferon gene signature is a peripheral blood signature derived from a genome-wide gene expression study. It is used to study the pharmacodynamic effects of Saphnelo by providing an indication of inhibition of type I interferon signaling after treatment.

[0125] The IFN21 gene signature (IFNGS) is a validated pharmacodynamic marker of type I IFN signaling

[10] (Figure 28), which is elevated in patients with type I IFN-mediated diseases, including SLE, lupus nephritis, myositis, Sjögren's disease, and scleroderma (Figures 31A and 31B).

[0126] A 4-gene IFNGS score is calculated by measuring the expression of IFI27, IFI44, IFI44L, and RSAD2. A 5-gene IFNGS score is calculated by measuring the expression of IFI27, RSAD2, IFI44, IFI44L, and IFI6. A 21-gene IFNGS score is calculated by measuring the genes shown in Figure 28. Gene expression can be measured by detecting mRNA in a subject's whole blood or tissue. An IFNGS (4-gene, 5-gene, or 21-gene) score can be detected in a subject by measuring IFNGS gene expression (e.g., mRNA) in the subject's blood or tissue and comparing the gene expression level to the expression of housekeeping or control genes, such as ACTB, GAPDH, and 18S rRNA, in the blood or tissue.

[0127] 6. Example 1: Anifrolumab in the Clinic Eight blinded or open-label intravenous (IV) and subcutaneous (SC) studies have evaluated the safety of anifrolumab: six studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), one study in patients with systemic sclerosis (SSc) (Study MI-CP180), and one study in healthy volunteers (Study 06) (Table 6-1). Two of these studies (Studies 08 and 06) used SC anifrolumab administration. Two studies are ongoing: one in patients with SLE (Study 09) and one in patients with lupus nephritis (LN) (Study 07).

[0128] [Table 5]

[0129] Study MI-CP151 is described in more detail in Higgs et al. 2013

[10] . Study 1013 is described in more detail in Furie et al. 2017

[19] , which is incorporated herein by reference in its entirety. Study 04 is described in more detail in Furie et al. 2019

[20] , which is incorporated herein by reference in its entirety. The results of Study 05 are presented in Morand et al. 2020

[21] , which is incorporated herein by reference in its entirety. A complete summary of the evidence for the clinical efficacy of intravenous anifrolumab in SLE is presented in Tanaka et al., 2020

[22] , which is incorporated herein by reference in its entirety.

[0130] 7. Example 2: Safety and Efficacy of Intravenous Anifrolumab 7.1.Validity The primary evaluation of anifrolumab's efficacy was based on data from three comprehensive, randomized, double-blind, placebo-controlled studies (Phase 3 Studies 04 and 05, and Phase 2 Study 1013). These studies were similar in design, involving a 52-week treatment period, with similar patient characteristics and consistent inclusion / exclusion criteria. The primary objective of all three studies was to evaluate the effect of anifrolumab compared to placebo on overall disease activity. Secondary objectives were selected to further characterize the efficacy of anifrolumab compared to placebo (e.g., ability to reduce glucocorticoid use, effects on organ-specific endpoints (skin SLE activity and joints), and flare rate).

[0131] Across three double-blind, comprehensive Phase 2 / 3 studies (Studies 04, 05, and 1013), the efficacy of anifrolumab 300 mg IV Q4W in patients with moderate to severe SLE was observed across a range of clinically important endpoints. Anifrolumab demonstrated early and sustained effects on overall disease activity, the ability to taper steroid use to clinically beneficial levels (≤7.5 mg / day) and maintain these levels through Week 52, early and sustained benefits on cutaneous skin activity, and clinically meaningful reductions in flare rates.

[0132] 2.1.1: Research 1013 (MUSE, NCT01438489) Study 1013 (MUSE, NCT01438489) was a phase 2b, multicenter, double-blind, randomized, placebo-controlled, 52-week study of anifrolumab 300 mg and 1000 mg compared with placebo in adult patients with moderately to severely active SLE despite standard of care (SOC) therapy. Tapering of OCS was encouraged during the study at the investigator's discretion. The primary efficacy endpoint was based on reduction in SLE disease activity, as measured by the SRI (4), including a sustained reduction in OCS use after 24 weeks of treatment.

[0133] The primary endpoint of a composite SRI(4) response, including sustained OCS reduction at week 24, was met in more patients receiving anifrolumab (34.3% and 28.8% of patients receiving 300 mg [n=99] and 1000 mg [n=104], respectively) than in placebo (17.6% [n=102] for 300 mg and 1000 mg vs. placebo, respectively; p=0.014 and p=0.063). Higher effect sizes were observed in patients with higher baseline IFNGS (36.0% (p=0.004) and 28.2% (p=0.029) of patients treated with anifrolumab 300 mg and 1000 mg, respectively), who achieved the primary endpoint (vs. 13.2% of patients receiving placebo). In patients with low baseline IFNGS, the response rates of patients achieving the primary endpoint were 29.2%, 30.8%, and 30.8% for anifrolumab 300 mg, anifrolumab 1000 mg, and placebo, respectively.

[0134] Study 1013 is described in more detail in Furie et al. 2017

[19] , which is incorporated herein by reference in its entirety.

[0135] 7.1.1. Studies 04 and 05 (TULIP I and TULIP II) The pivotal TULIP (Treatment of Uncontrolled Lupus via the IFN Pathway) program included two phase 3, multinational, randomized, double-blind, placebo-controlled, parallel-group clinical trials, TULIP-1 (Study 04) and TULIP-2 (Study 05). The designs of Studies 04 and 05 were nearly identical (Figure 1). Both studies consisted of a 52-week treatment period, including a total of 13 doses of anifrolumab or placebo IV Q4W from Week 0 to Week 48. The primary endpoint was assessed at Week 52. OCS tapering was mandatory for patients receiving baseline oral prednisone ≥ 10 mg / day or equivalent in both studies until a dosage of ≤ 7.5 mg / day was achieved from Week 8 to Week 40, and this dose had to be sustained through Week 52. The following composite endpoints that detected clinically meaningful improvements in SLE disease activity were used in both studies: SRI(4) (primary endpoint in TULIP-1) and BICLA (primary endpoint in TULIP-2).

[0136] The selection of anifrolumab at a dose of 300 mg once every four weeks (Q4W) for these studies was based on safety and efficacy results from an interim analysis of the Phase 2b 1013 study, in which two doses of anifrolumab (300 mg and 1000 mg) were evaluated compared to placebo, as well as dose-response modeling and simulations (as described in U.S. Patent No. 9,493,570, corresponding to International Publication No. WO 2013188494, incorporated herein by reference in its entirety). In the interim analysis of the Phase 2b study, a clinically significant benefit was observed at the 300 mg dose, with no incremental benefit at 1000 mg. Additionally, a greater proportion of subjects reported reactivation of shingles at 1000 mg compared to 300 mg. Given the similar efficacy of the 300 mg and 1000 mg doses of anifrolumab and the increased frequency of shingles in the 1000 mg dose group compared with the 300 mg dose group, the benefit / risk profile appears to favor the 300 mg dose.

[0137] In TULIP-1 and TULIP-2, patients with moderate to severe SLE despite standard therapy were randomized to receive intravenous anifrolumab 300 mg (TULIP-1 and TULIP-2), anifrolumab 150 mg (TULIP-1 only), or placebo Q4W for 48 weeks in parallel with standard therapy. Randomization was based on Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score at screening (<10 vs. ≥10), 4-gene IFNGS status (high vs. low), and baseline oral glucocorticoid dosage (<10 vs. ≥10 mg / day). -1 The TULIP-1 and TULIP-2 trials had consistent efficacy variables, safety variables, frequency of assessments, and inclusion / exclusion criteria (Figure 1).

[0138] 7.1.2. Research 04 (TULIP I, NCT02446912) Study 04 compared anifrolumab 150 mg and 300 mg with placebo in adult patients with moderately to severely active SLE despite receiving standard of care therapy. Efficacy was assessed based on reduction in SLE disease activity as measured by SRI(4) response.

[0139] In Study 04, the proportion of patients achieving the primary outcome of SRI(4) response at week 52 was similar between the anifrolumab 300 mg group (84 / 180 [47%]) and the placebo group (79 / 184 [43%]) (difference: 3.9; 95% CI: 6.3, 14.1; p=.45) (Figure 2). Similarly, in a prespecified analysis (unmodified prohibited substance rule), the proportion of patients with an SRI(4) response at week 52 was 65 of 180 patients (36%) treated with anifrolumab 300 mg compared with 74 of 184 patients (40%) in the placebo group (difference: 4.2; 95% CI: 14.2, 5.8; p=.41).

[0140] Study 04 is described in more detail in Furie et al. 2019

[20] , which is incorporated herein by reference in its entirety.

[0141] 7.1.3. Research 05 (TULIP II, NCT02446899) In Study 05 (TULIP-2), a protocol amendment changed the primary endpoint from SRI(4) to BICLA response before unblinding the study data and after completion of TULIP-1. This change was informed by the MUSE and TULIP-1 analyses.

[0142] Study 05 compared anifrolumab 300 mg with placebo in adult patients with moderately to severely active SLE despite receiving standard of care (SOC) treatment. Efficacy in this study was assessed based on reduction in SLE disease activity as measured by BILAG-based Composite Lupus Assessment (BICLA) response.

[0143] In Study 05, a higher proportion of patients in the anifrolumab group (47.8%) than in the placebo group (31.5%) achieved the primary outcome of BICLA response at week 52 (adjusted difference: 16.3%; 95% CI: 6.3, 26.3; p=.001) (Figure 2, Figure 3A, and Figure 3B). In the high IFNGS subgroup, the proportion of patients with a BICLA response at week 52 was 48.0% (72 / 150) in the anifrolumab group and 30.7% (46 / 151) in the placebo group (adjusted difference: 17.3%; 95% CI: 6.5, 28.2; adjusted p=.002). Corresponding results for the lower IFNGS outcome subgroups were 46.7% (14 / 30) and 35.5% (11 / 31) of patients in the anifrolumab and placebo groups, respectively (adjusted difference: 11.2; 95% CI: 13.5, 35.8). There was homogeneity in BICLA responses favoring anifrolumab across other protocol-defined patient subgroups of baseline disease severity, race, ethnicity, age, sex, age at disease onset, and antidrug antibody status. The HR for time to achieving a sustained BICLA response by week 52 in the overall population favored anifrolumab 300 mg over placebo (HR: 1.55; 95% CI: 1.11, 2.18).

[0144] Anifrolumab also demonstrated significant benefit in sustained reduction of OCS and reduction in skin disease severity (reduced CLASI score) (Figure 2). Among patients receiving prednisone ≥ 10 mg / day or equivalent at baseline, 51.7% (45 / 87) of patients treated with anifrolumab and 30.1% (25 / 83) of those receiving placebo achieved a sustained reduction to ≤ 7.5 mg / day (adjusted difference: 21.2%; 95% CI: 6.8, 35.7; adjusted p = .01). Among patients with at least moderately active skin disease (CLASI score ≥ 10) at baseline, 49.0% (24 / 49) of those receiving anifrolumab and 25.0% (10 / 40) of those receiving placebo experienced a ≥ 50% reduction in CLASI score at week 12 (adjusted difference: 24.0%; 95% CI: 4.3, 43.6; adjusted p = .04). Although treatment response in organs other than skin and joints was not part of the prespecified analysis, the definition of BICLA response required improvement in all organ systems affected at baseline (reduction of all baseline BILAG-2004 A and B domain scores to B / C / D and C / D, respectively) and the absence of new flares in the remaining BILAG-2004 organ systems. At baseline, the most commonly affected organ systems in enrolled patients were mucocutaneous and musculoskeletal (>80% involved BILAG-2004 A or B). Baseline BILAG-2004 A or B scores occurred less frequently in the cardiopulmonary, systemic, renal, neuropsychiatric, gastrointestinal, hematological, and ocular systems. Thus, by definition, responses occurred in all affected BILAG-2004 organ systems in patients who achieved a BICLA response. The annualized flare rate based on BILAG-2004 was 0.43 in the anifrolumab group and 0.64 in the placebo group (adjusted rate ratio: 0.67; 95% CI: 0.48, 0.94; adjusted p = .08)

[37] . Among patients with ≥6 swollen joints and ≥6 tender joints at baseline, 42.2% (30 / 71) in the anifrolumab group and 37.5% (34 / 90) in the placebo group (adjusted difference: 4.7%; 95% CI: 10.6, 20.0; adjusted p=0.55) had a ≥50% reduction in both the number of swollen and tender joints at week 52.

[0145] The results of Study 05 are presented in Morand et al. 2020

[21] , which is incorporated herein by reference in its entirety.

[0146] 7.1.4. Efficacy Conclusions Study 05 provided strong evidence of the efficacy of anifrolumab for the treatment of patients with moderately to severely active SLE despite receiving standard of care therapy, based on the pre-specified BICLA primary endpoint. Combined data from all three clinical trials further support the efficacy of anifrolumab 300 mg in these patients across a wide range of clinically significant endpoints. Importantly, there was a consistent benefit of anifrolumab 300 mg in BICLA response rate studies at week 52. A treatment difference of >16% compared with placebo was observed in BICLA response rates in all three studies. Furthermore, anifrolumab suggested a treatment benefit on SRI(4) response in both TULIP-2 and MUSE. The consistent and supportive evidence of efficacy of anifrolumab 300 mg across many key secondary endpoints (e.g., reduction in OCS, improvement in CLASI score, reduction in flares) is relevant to characterize the full extent of anifrolumab's treatment effect, especially given the heterogeneity of SLE manifestations.

[0147] Anifrolumab has demonstrated efficacy in reducing flare rates, with the onset of treatment effect in reducing disease activity occurring as early as 8 to 12 weeks after treatment initiation, when a >10% numerical separation in BICLA response rates was observed in favor of anifrolumab 300 mg and maintained throughout 52 weeks of treatment. Furthermore, the steroid-sparing effect of anifrolumab may reduce the cumulative risk of long-term organ damage associated with SLE. The improvement in cutaneous manifestations (CLASI activity score) seen with anifrolumab treatment is also particularly significant, as cutaneous manifestations are common and often involve the face, head, and neck, with visible involvement.

[0148] A complete summary of the evidence for the clinical efficacy of intravenous anifrolumab in SLE is presented in Tanaka et al., 2020, which is incorporated herein by reference in its entirety.

[0149] 7.2. Safety The safety and tolerability of anifrolumab were consistent and generally similar across all three efficacy studies. The percentage of patients experiencing any adverse events (AEs) ranged from 85% to 89% across studies in those treated with anifrolumab and 77% to 84% in those receiving placebo. The most common AEs included upper respiratory tract infection, nasopharyngitis, and infusion-related reactions. Anifrolumab infusions were generally well tolerated, with one report of anaphylaxis occurring in a patient receiving anifrolumab 150 mg in TULIP-1. Only a few patients experienced hypersensitivity, and most infusion-related AEs were not serious and were mild or moderate in intensity. Serious AEs (SAEs) occurred in 8% to 16% of patients treated with anifrolumab and 16% to 19% of patients receiving placebo. There was one death each during the treatment period of TULIP-1 and TULIP-2, both of which occurred in the anifrolumab-treated group and were due to pneumonia. There was also one death in MUSE in a patient who received a single 1000 mg dose of anifrolumab and had acute colitis. The proportion of patients with AEs leading to discontinuation was smaller among those receiving anifrolumab versus placebo in TULIP-2 and MUSE, but greater among patients treated with anifrolumab in TULIP-1 (6% versus 3% for placebo).

[0150] The incidence of herpes zoster was increased in the anifrolumab-treated group (5-7%) compared with the placebo group (1-2%); most incidents were cutaneous, non-serious, and did not lead to discontinuation. All responded to SOC treatment and generally resolved without sequelae. For other AEs of particular interest, incidence was low and similar between treatment groups.

[0151] A complete summary of the evidence on the safety and tolerability of anifrolumab is presented in Tanaka et al., 2020, which is incorporated herein by reference in its entirety.

[0152] 7.3. Conclusion Anifrolumab demonstrated clinically relevant benefit in subjects with moderate to severe SLE treated with SOC. Its efficacy was supported by a wide range of overall (various levels of SRI response, BICLA) and organ-specific disease activity (CLASI, joint count) clinical measures. A clinically relevant increase in the proportion of subjects achieving a pre-specified corticosteroid reduction was also observed in the 300 mg group compared with placebo, but no clear difference was observed when comparing the 1000 mg group with placebo.

[0153] Anifrolumab was generally well tolerated. A dose-dependent increase in the number of subjects with herpes zoster uncomplicated infections was also observed in subjects receiving anifrolumab compared with placebo.

[0154] BICLA responses, as well as sustained OCS reductions and CLASI improvements, were consistently achieved in greater numbers in patients receiving anifrolumab compared with placebo across all three studies. A greater proportion of patients also achieved SRI(4) responses with anifrolumab compared with placebo in both MUSE and TULIP-2. The safety profile of anifrolumab was generally similar across efficacy studies, with SAEs occurring in 8-16% of patients treated with anifrolumab and 16-19% of patients receiving placebo. In all three studies, the incidence of herpes zoster was increased in the anifrolumab-treated groups compared with the placebo group, but most occurrences were cutaneous manifestations and responded to SOC treatment. Evidence from the described clinical trials suggests that anifrolumab 300 mg administered IV Q4W is superior to placebo in achieving the composite endpoint of disease activity response, as well as reducing OCS dosage, skin disease severity, and flare rate in patients with active SLE. Thus, clinical studies of anifrolumab IV administration concluded that 300 mg IV Q4W was the optimal dose compared with 150 mg Q4W. Increasing the dose to 1000 mg Q4W was found to provide only incremental benefit, and a dose-dependent increase in herpes zoster infections was observed (Figure 4).

[0155] 8. Example 3: Subcutaneous administration of anifrolumab 8.1. MI-CP180, a Phase 1 Study of IV Anifrolumab in Patients with SSc The mean anifrolumab serum concentrations after single-dose administration based on body weight are shown in Figure 5A. After single-dose administration, anifrolumab demonstrated nonlinear to linear PK at lower dose levels (<10.0 mg / kg) in both high-IFNGS and low-IFNGS patients. max A dose-proportional increase in AUC was observed, but the increase in AUC was greater than dose-proportional at 0.1 to 10.0 mg / kg. The t1 / 2 of anifrolumab was more prolonged in the higher dose cohorts. At the highest dose level studied (20.0 mg / kg), the terminal t1 / 2 was approximately 12 days.

[0156] 8.2. Phase 1 of IV and SC Anifrolumab in Healthy Volunteers (Study 06) In this phase 1, randomized, placebo-controlled study, 30 healthy adults were assigned to three treatment cohorts: anifrolumab 300 mg SC (n = 6), anifrolumab 300 mg IV (n = 6), and anifrolumab 600 mg SC (n = 6)) and placebo (n = 4 / cohort). After SC administration, exposure to anifrolumab was proportionally increased from 300 mg to 600 mg based on the area under the serum concentration-time curve. The arithmetic mean serum anifrolumab concentration-time profiles after single IV and SC administration are shown in Figure 5B. As reported by Tummala et al. 2018 [8] (incorporated herein by reference in its entirety), this study estimated the bioavailability of anifrolumab in healthy volunteers to be 87% following intravenous exposure.

[0157] 8.3. Phase 2 Study of SC Anifrolumab in Patients with SLE (Study 08) This study was designed to characterize the pharmacokinetics and pharmacodynamics of subcutaneously administered anifrolumab (Figure 6A).

[0158] This study investigated the clinical pharmacology, safety, and exploratory efficacy of subcutaneous anifrolumab. The pharmacokinetics in Study 08 were consistent with the high bioavailability in Study 06 (healthy volunteers) and the high CL in patients with high IFNGS and SLE. Anifrolumab administered subcutaneously once every two weeks to patients with SLE and moderate to severe skin manifestations had nonlinear pharmacokinetics that exceeded dose proportionality and neutralized the type I interferon gene signature in a dose-dependent manner (Figures 6B and 6C). Notably, subcutaneous anifrolumab at 150 mg or 300 mg administered once every two weeks for 50 weeks had nonlinear pharmacokinetics, thereby neutralizing the C. トラフ Concentrations were more than dose-proportional. The number of adverse events associated with subcutaneous anifrolumab was similar to that observed after intravenous administration in a larger study of patients with SLE.

[0159] The results of Study 08 are described in detail in Bruce et al.

[23] , which is incorporated herein by reference in its entirety.

[0160] Study 08 was limited by a smaller sample size, which prevented any conclusions from being drawn about the biological effects of the study drug (e.g., on complement C3 or C4 levels) or its clinical efficacy. Also, the inclusion of only patients with a high type I interferon gene signature and active skin disease limited the generalizability of the study to patients with similar disease characteristics. This study was further limited by the increasing frequency of missing values ​​over time.

[0161] 8.4. Conclusion The PK of anifrolumab consistently demonstrated target-mediated pharmacokinetics, with concentrations or exposure decreasing more than dose-proportionally at lower dose levels. In Study 06 (healthy volunteers), high bioavailability of anifrolumab administered by SC injection was observed. The AUC ratio of anifrolumab SC to anifrolumab IV at less than 300 mg was approximately 87%.

[0162] 9. Example 4: Determination of Optimal Subcutaneous Unit Dose 9.1. Purpose To find the optimal dosing regimen for subcutaneous administration of anifrolumab, we developed a population PK and PK / PD model designed to utilize existing human clinical trials. PK data from Phase 3 studies 04 and 05 and Phase 2 study 1013 were used to support the development of the population PK model.

[0163] Our initial goal was to find a subcutaneous dose that would provide equivalent exposure to the standard 300 mg IV (Q4W) dose and concomitantly allow for more regular dosing that could be provided in smaller amounts. This was based on the understanding that 300 mg IV Q4W provides an optimal PK profile and clinical efficacy (e.g., in terms of achieving a BICLA response), as reported, for example, in Furie et al. 2017

[19] , which is incorporated herein by reference in its entirety.

[0164] 9.2.Results 9.2.1 Initial Selection of Subcutaneous Anifrolumab Dose In an initial analysis, we determined specific dosing regimens predicted to provide exposure equivalent to that achievable with 300 mg Q4W IV. Initially, we found that a 105 mg subcutaneous once-weekly (QW) dosing regimen provided an AUC ratio close to (or slightly higher than) 1 (Figure 7A), even though the predicted bioavailability was reduced by approximately 7% compared to that reported by Tummal et al. 2018 [8] (incorporated herein by reference in its entirety) to account for interindividual variability in bioavailability (Figure 7B). 105 mg subcutaneous QW appeared to provide comparable or improved median trough concentrations and IFNGS suppression compared to the comparative 300 mg Q4W IV dose (Figures 8A and 8B). From these initial analyses, it was believed that the SC 105 mg QW dose of anifrolumab should be selected as the equivalent of 300 mg Q4W and therefore as having the optimal efficacy / risk profile for treating patients with SLE. Importantly, these analyses inferred that the 300 mg IV dose was on or near the plateau of the anifrolumab dose-response curve, i.e., that increasing the dose above 300 mg IV Q4W would not provide any significant benefit to patients, especially considering the increased risk of herpes zoster infection at higher doses.

[0165] 9.2.2. Modified Subcutaneous Anifrolumab Dose Selection Therefore, we initially considered 105 mg QW to be the optimal SC dose of anifrolumab for the treatment of type I IFN-mediated diseases based on the available data from the MUSE study, Study 06, and Study 08. However, to confirm the selection of the 105 mg SC dose, we conducted further analyses of data from the TULIP I (Study 04) and TULIP II (Study 05) clinical trials.

[0166] Additional data were used to demonstrate the positivity-exposure-BICLA association in patients with high IFNGS. Surprisingly, this association was observed even in the 300 mg IV Q4W group (Figures 9A and 9B). Thus, BICLA response within the 300 mg IV Q4W patient group was variable. Logistic regression of BICLA response at Week 52 in patients confirmed that PK exposure was a significant covariate in both TULIP I and TULIP II. ave was found to be statistically significant in both the analysis of all participants who completed treatment and high IFNGS in both TULIP I and TULIP II independently, as well as in the pooled TULIP I and TULIP II analyses. ave Exposure-response demonstrating a higher BICLA and SRI(4) correlated with a higher BICLA and SRI(4). In other words, there was exposure-dependent variability in response to anifrolumab among lupus patients receiving 300 mg Q4W IV (Figures 9A and 9B).

[0167] Surprisingly, the 300 mg IV Q4W dose was therefore found to be at the onset of the exposure-response plateau, while the suboptimal 150 mg IV dose was in the step region of the exposure-response curve ( FIG. 10A ). As a result of these analyses, the inventors determined that the 105 mg QW subcutaneous dose (previously considered equivalent to the 300 mg IV Q4W dose) did not provide an optimal balance of efficacy and safety in lupus patients. Therefore, the inventors decided to select an alternative dose for SC administration that would mitigate the impact of response variability in the lupus patient population.

[0168] In summary, from the initial analysis, the administration of a subcutaneous dose of 105 mg QW anifrolumab appears to achieve at least similar efficacy to that of 300 mg IV Q4W. However, surprisingly, after the inventors further analyzed newly available data from further studies, it was found that the concentration of this once-weekly (QW) dose can be increased without reaching the maximum threshold in terms of bioavailability and efficacy. In other words, to provide higher plasma concentration and IFNGS suppression and to alleviate the variability observed in response in SLE patients, the QW dose may be increased to more than 105 mg. Therefore, the dose of 105 mg is suboptimal.

[0169] This surprising additional dose-response curve data was further substantiated by demonstrating an increased probability of achieving a relevant BICLA response (in patients with high IFNGS) when administered subcutaneously once weekly at concentrations above the 105 mg dose (Table 9-1). These data demonstrate the unexpected location of the dose-response plateau (e.g., under subcutaneous administration), which shifts to the right with increasing doses above 105 mg (Figure 10B), indicating that the maximum BICLA response is indeed achievable at doses above 105 mg, and that higher doses are preferred (Table 9-1).

[0170] [Table 6]

[0171] 9.2.3. Anifrolumab Bioavailability is Highly Variable Further investigation into the bioavailability of anifrolumab revealed that a surprisingly high level of variability in the bioavailability of anifrolumab after subcutaneous administration may exist among different patients. This high level of variability in the bioavailability of anifrolumab was not observed in previous studies reporting bioavailability of >80% after subcutaneous administration (see Example 3) [8]. The bioavailability (F1) of anifrolumab in Study 08 (SLE patients, SC) was found to be 81% in healthy volunteers using a population PK model (Table 9-2).

[0172] [Table 7]

[0173] We conducted an external validation of Study 08, a Phase 2 SC in SLE, using the PPK model developed in healthy volunteers from the IV study and SLE patients to determine bioavailability in the lupus population.

[0174] A thorough analysis of the data from Study 08 revealed that bioavailability was affected by the site of SC administration. Specifically, when extrapolating the bioavailability of 300 mg in the abdomen versus IV, the bioavailability (F1) was estimated to be 85.4% compared to 81% when injection site was not taken into account. Thus, C after thigh injection トラフThe C tended to be lower compared to abdominal injection (Figures 11A and 11B). Thus, it was surprisingly concluded that bioavailability could actually be as low as 70% when taking into account the variability due to injection site and the higher variability in bioavailability in lupus (SLE) patients compared to healthy volunteers. Importantly, assuming a bioavailability (F1) of 81-87%, 105 mg had a C comparable to 300 mg IV. ave (Figure 12). In contrast, the C of a 105 mg QW subcutaneous dose was predicted to be approximately 70% or less when the estimated bioavailability was reduced. ave The median value fell to less than 1 (Figures 13A, 13B, and Table 9-3).

[0175] [Table 8]

[0176] Furthermore, there was no significant difference in C between 105 mg SC QW and the suboptimal IV dose of 150 mg Q4W. ave There was an undesirable 30% overlap when the SC dose was used, whereas only a 16% overlap was observed when a bioavailability of 81% was assumed (Figure 13A). However, when the SC 120 mg dose was used, there was a significant difference in C with the 150 mg IV dose. ave The overlap was less than that with the optimal IV dose of 300 mg IV, even assuming a low bioavailability of 70% (Figure 13B). Furthermore, the 120 mg SC QW dose had minimal overlap with the undesirable 1000 mg IV dose (Figure 15), where the risk of shingles infection increases (Figure 15). The 150 mg SC QW dose had undesirable overlap with the 1000 mg IV Q4W dose. Even more surprisingly, SC doses of 120 mg and above were predicted to have better PD suppression (Table 9-4) than the assumed optimal 300 mg IV dose (Table 9-5).

[0177] Therefore, selecting a dose above 105 mg, preferably 120 mg or greater, optimizes exposure response by minimizing the impact of variability in response onset and bioavailability in patients with lupus (e.g., SLE) (Table 9-4, Figures 14A, 14B). SC doses below 150 mg QW are also desirable to reduce the risk of herpes zoster infection (Figure 15).

[0178] [Table 9]

[0179] [Table 10]

[0180] In particular, the doses of 120 mg and 135 mg QW offer a reasonable benefit / risk profile. Given that a SC dose of 150 mg QW is equivalent to 1000 mg IV Q4W, doses of 150 mg QW or higher increase safety risks, such as an increased risk of shingles in patients (Figures 13C, 15A). Therefore, subcutaneous doses of less than 150 mg QW and greater than 105 mg QW were determined as preferred doses. Subcutaneous doses of less than 150 mg QW and less than or equal to 135 mg were determined as more preferred doses. The subcutaneous dose of 120 mg was determined as the optimal dose.

[0181] In summary, the inventors, considering previously available preliminary data, discovered for the first time that the optimal subcutaneous dose of anifrolumab appears to be 105 mg QW ( FIG. 15 ). However, further data and analysis surprisingly revealed that doses below 105 mg QW resulted in inadequate dosing in a significant proportion of patients ( FIG. 10B , Table 9-3). Thus, the particularly advantageous dosing regimen demonstrated by the inventors was a dose above 105 mg QW. In particular, the optimal dose was determined to be 120 mg subcutaneous QW, which, depending on estimated bioavailability, is equivalent to approximately 400 mg IV Q4W. Thus, the optimal SC dose is surprisingly >30% higher than that considered optimal based solely on the comparison with 300 mg IV Q4W and the previously understood bioavailability of anifrolumab. In other words, data from Study 06 (300 mg IV vs. 300 mg and 600 mg SC (abdominal)) suggest that the bioavailability of anifrolumab is approximately 86% (300 mg SC compared to 300 mg IV). Surprisingly, however, further analysis of Study 08 (150 mg and 300 mg SC Q2W) revealed that C トラフ It was found that the bioavailability tended to be lower compared to abdominal injection. Therefore, without taking the injection site into consideration based on modeling and simulation, the bioavailability was estimated to be about 81%, but could be as low as 70% when justifying SC dose selection above 105 mg QW (Figure 14).

[0182] Therefore, the inventors have surprisingly demonstrated that doses greater than 105 mg SC QW and less than 150 mg SC QW, particularly a dose of 120 mg QW, (a) maximize efficacy while maintaining an acceptable safety profile, (b) mitigate the impact of bioavailability variability, and (c) mitigate the impact of variability in response onset. Thus, dosages greater than 105 mg QW advantageously account for bioavailability variability, resulting in improved therapeutic outcomes. Doses less than 150 mg QW mitigate the risk of herpes zoster infection.

[0183] Pharmacokinetic data from healthy volunteers (Study 06 (IV treatment group only)) and SLE patients (Studies 1013, 02, 04, and 05) were also pooled to assess the impact of covariates, such as demographics and renal / liver function tests, on PK exposure. Patients with higher body weight and higher type I IFN test results were found to have significantly higher clearance (CL) and lower concentrations. Surprisingly, however, there was no clinically relevant impact of these covariates on efficacy and safety. Surprisingly, other covariates associated with specific populations assessed in population PK modeling, such as race / ethnicity / region, age, sex, renal / liver function tests, standard of care therapies (e.g., OCS, antimalarials, azathioprine, methotrexate, mycophenolate mofetil, mycophenolate, mizoribine, and NSAIDs), and medications commonly used in SLE patients (ACE inhibitors and HMG-CoA reductase inhibitors), were found to be insignificant.

[0184] 9.3. Conclusion We demonstrate that anifrolumab doses <150 mg Q and >105 mg QW have at least similar, or even higher, C values ​​over 52 weeks than 300 mg IV Q4W. ave In particular, the 120 mg SC QW dose provides efficacy at least equivalent to that demonstrated with the 300 mg IV Q4W dose in lupus patients. Furthermore, the 120 mg SC QW dose has been reasonably demonstrated to provide efficacy greater than that demonstrated with the 300 mg IV Q4W dose.

[0185] Based on the data demonstrated herein, a subcutaneous dose of anifrolumab was selected for a multicenter, randomized, double-blind, placebo-controlled, phase 3 study evaluating the efficacy and safety of subcutaneous anifrolumab in adult patients with SLE. In summary, two doses of SC anifrolumab (150 mg and 300 mg once every 2 weeks (Q2W)) were evaluated in a completed phase 2 SC study (Study 06) in SLE patients with high type I IFN testing and active skin disease. The primary pharmacokinetic (PK) / pharmacodynamic (PD) endpoint of the phase 2 SC study was analyzed at week 12, and the safety and tolerability of SC administration of anifrolumab was evaluated through week 52. Based on the PK / PD data from the phase 2 SC study and data from the anifrolumab IV study, mean concentrations (C) of anifrolumab were comparable and non-inferior to a single 300 mg IV injection. ave The 120 mg QW dose was selected for this current Phase 3 SC study to provide efficacy at least similar to that of 300 mg IV Q4W.

[0186] Considering the change in dosing interval from Q4W to QW, and at least a similar C ave By providing 120 mg SC QW, trough concentrations are predicted to be higher than those of 300 mg IV Q4W, and therefore are expected to provide comparable PD suppression to that of 300 mg IV. In addition, the C of 120 mg SC QW over 52 weeks ave has been shown to be safe and tolerable (evaluated in Phase 2b study 1013) ave has minimal overlap with 1000 mg IV Q4W, and therefore any dose equivalent to less than 1000 mg IV Q4W is considered safe.

[0187] The development of an SC administration route using the APFS of an AI for anifrolumab is expected to improve convenience and dosing flexibility, reduce patient and / or caregiver exposure to infection risks (including, but not limited to, influenza or COVID-19) associated with visiting a clinic for medication administration, and improve access to and compliance with treatment.

[0188] 10. Example 5: Relationship between pharmacokinetics, pharmacodynamics, and efficacy of anifrolumab in patients with moderate to severe systemic lupus erythematosus Overview This study aimed to elucidate the pharmacokinetic / pharmacodynamic and pharmacodynamic / efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE). Data were pooled from the randomized, 52-week, placebo-controlled TULIP-1 and TULIP-2 trials of intravenous anifrolumab (150 mg / 300 mg, once every four weeks for 48 weeks (Q4W)). Pharmacodynamic neutralization in patients with high IFNGS was measured using the 21-gene type I interferon gene signature (21-IFNGS). Pharmacokinetic / pharmacodynamic relationships were analyzed graphically and modeled with nonlinear mixed-effects models. British Isles Lupus Assessment Group-Based Integrated Lupus Assessment (BICLA) response rates were compared across 21-IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 had high IFNGS. Over 52 weeks, higher mean anifrolumab serum concentrations were associated with higher median IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12–52), low and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. IC at week 24 80 Anifrolumab trough concentrations (C トラフ The proportion of patients with CR was higher with anifrolumab 300 mg than with anifrolumab 150 mg (approximately 83% vs. approximately 27%), which is related to a higher estimated C トラフThe median BICLA response rate increased with 21-IFNGS neutralization. More patients had a BICLA response in the highest versus lowest neutralization quartile at Week 52 (58.1% versus 37.6%). In summary, anifrolumab IV 300 mg Q4W rapidly, substantially, and sustainably neutralized 21-IFNGS, and this was associated with supportive clinical efficacy for the 300 mg IV dosing regimen and the corresponding 120 mg SC dose in SLE patients.

[0189] Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune condition characterized by dysregulation of innate and adaptive immune pathways, hyperinflammatory signaling cascades, and immune deposits in tissues, which can cause irreversible damage to vital organs. The type I interferon (IFN) signaling pathway plays a key role in the pathogenesis of SLE. All five classes of type I IFNs (α, β, ε, κ, and ω) activate the type I IFN-α receptor (IFNAR), which mediates downstream signaling that stimulates IFN-regulated gene transcription, as measured using the IFN gene signature (IFNGS). High levels of type I IFNGS in blood or tissues occur in 50–80% of SLE patients and are associated with increased disease activity. 10~13 High IFNGS patients have more active SLE disease with higher levels of anti-double-stranded DNA (anti-dsDNA) antibodies compared to low IFNGS patients.

[0190] Anifrolumab is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody that binds with high affinity and specificity to type I IFNAR subunit 1 (IFNAR1) and sterically inhibits the formation of functional IFNAR complexes. The ensuing antibody-receptor complex is rapidly internalized, preventing IFNAR1-mediated signaling in response to all classes of type I IFNs.

[0191] In the randomized, placebo-controlled, 52-week phase 3 TULIP-1 and TULIP-2 trials, intravenous anifrolumab 300 mg once every 4 weeks (Q4W) for 48 weeks was well tolerated and more effective than placebo across a wide range of clinical endpoints, including British Isles Lupus Assessment Group (BILAG)-based Integrated Lupus Assessment (BICLA) response, skin response, oral glucocorticoid dosage reduction, and flare rate, in patients with moderate to severe SLE despite receiving standard of care. In line with the proposed mechanism of action, anifrolumab 300 mg induced substantial (median >85%) pharmacodynamic (PD) neutralization of 21-gene type I IFNGS (21-IFNGS) in patients with high IFNGS, which was achieved as early as week 4 and sustained through week 52.

[0192] In an analysis of anifrolumab pharmacokinetic (PK) exposure across five clinical trials, median anifrolumab serum concentrations at 300 mg Q4W were consistent throughout the 52-week treatment period (across studies and within each study), with trough concentrations below the limit of quantitation (C トラフ Few patients had high IFNGS expression. High IFNGS expression was associated with lower systemic anifrolumab exposure, as patients with high IFNGS had a shorter median time to elimination than patients with low IFNGS (57 days vs. 67 days). Anifrolumab PK concentrations were also inversely correlated with body weight but were not affected by other covariates tested (race, age, sex, renal and hepatic function, immunogenicity, and use of common SLE medications).

[0193] In patients with systemic sclerosis and SLE, higher anifrolumab dosage correlated with higher PD neutralization, but the PK / PD and PD / efficacy relationships, and whether they were influenced by disease characteristics, have not yet been fully characterized. Herein, we aimed to confirm that the proposed recommended dosage, intravenous anifrolumab 300 mg Q4W dosing regimen, provides adequate PK exposure and PD neutralization in high-IFNGS patients with SLE. Because PD neutralization was quantified as a change from baseline 21-IFNGS score, we did not include low-IFNGS patients in our analysis because their baseline 21-IFNGS expression is insufficient to observe significant PD neutralization. To investigate PK and PD in patients with high IFNGS, we used pooled data from the TULIP-1 and TULIP-2 studies to evaluate how changes in serum anifrolumab exposure affect PD neutralization of 21-IFNGS and, in turn, how neutralization of 21-IFNGS correlates with clinical efficacy.

[0194] 10.3. Method 10.3.1. Research design For this analysis, data were pooled from the randomized, double-blind, parallel-group, placebo-controlled, 52-week phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) ​​trials (Figure 1).

[0195] 10.3.2.Patient The TULIP-1 and TULIP-2 trials enrolled adults (aged 18-70 years) who met the American College of Rheumatology (ACR) classification criteria for SLE. All patients had moderate to severe SLE, defined as a SLEDAI-2K score ≥6 (excluding points attributable to fever, lupus-related headache, or organic brain syndrome) and a clinical (not including laboratory results) SLEDAI-2K score ≥4. At screening, patients were seropositive for antinuclear antibodies, anti-dsDNA antibodies, and / or anti-Smith antibodies and received at least one stable standard of care treatment. At screening, patients were classified by a central laboratory as 4-gene type I high or low IFNGS using quantitative polymerase chain reaction (qPCR)-based testing of 4 genes (IFI27, IFI44, IFI44L, and RSAD2) derived from patient whole blood, as documented by analysis.

[0196] 10.3.3. Efficacy endpoints Both the TULIP-1 and TULIP-2 trials assessed the proportion of patients in the anifrolumab 300 mg group versus the placebo group with a BICLA response at week 52 (primary endpoint in TULIP-2, secondary endpoint in TULIP-1) or an SLE Responder Index (SRI(4)) of ≥ 4 responses at week 52 (primary endpoint in TULIP-1, secondary endpoint in TULIP-2). The proportion of patients classified as BICLA or SRI(4) responders, the differences between the anifrolumab and placebo groups, and the associated 95% confidence intervals (CIs) were adjusted for stratification factors using the Cochran-Mantel-Haenszel method.

[0197] BICLA response was defined as all of the following: reduction in all baseline BILAG-2004 A and B domain scores to B / C / D and C / D, respectively, and no deterioration in other BILAG-2004 organ systems; no increase (from baseline) in SLEDAI-2K score; no increase (from baseline) in Physician's Global Assessment (PGA) score (≥ 0.3 points from baseline); no discontinuation of study treatment; and no use of prohibited substances.

[0198] SRI(4) response was defined as all of the following: a ≥ 4-point reduction in the SLEDAI-2K; a new BILAG-2004 A or a new BILAG-2004 B organ domain score of < 1 or < 2; no increase in PGA score (≥ 0.3 points from baseline); no discontinuation of study treatment; and no use of prohibited substances.

[0199] 10.3.4. PK Measurement and Modeling The PK analysis dataset included all patients who received anifrolumab 150 mg or anifrolumab 300 mg and had at least one quantifiable serum PK observation after the first dose. PK measurements were obtained pre-dose at weeks 0, 12, 24, 36, and 48, and post-dose at 15 ± 5 minutes post-infusion at weeks 0 and 48, with a final anifrolumab PK measurement obtained at week 52. Anifrolumab concentrations were measured using an electrochemiluminescence assay on the Meso Scale Discovery platform (Meso Scale Diagnostics, Rockville, MD, USA). The assay range was 20–1280 ng / mL in 1:10 diluted human serum. -1 The lower limit of quantitation is 20 ng / mL. -1 As described above, a population PK model developed for SLE was used to predict predicted anifrolumab concentrations at specified time points (e.g., anifrolumab trough concentration at week 24 [C トラフ ] and predicted mean anifrolumab concentrations over the treatment period (C ave ) was estimated.

[0200] 10.3.5.PD Measurement As previously described, PD was measured using the 21-IFNGS assay, which consists of 21 type I IFN-α / β-inducible genes (Figure 28), including four genes in the dichotomous IFNGS test [24, 25]. PD measurements obtained at baseline were expressed as the median fold change in the 21-IFNGS score relative to a pooled healthy control sample from 30 healthy volunteers. PD was also measured at weeks 12, 24, 36, and 52, where median PD neutralization was expressed as the median percent change from baseline in the 21-IFNGS score + / - the median absolute deviation (MAD). All PD analyses excluded 25 patients for whom baseline PD measurements were missing.

[0201] PK / PD Analysis Patients with low IFNGS had baseline 21-IFNGS scores similar to those of healthy subjects, which would be insufficient to observe significant PD reversal, and therefore, patients with low IFNGS were not included in the PK / PD or PD / efficacy analyses.

[0202] 10.3.6.1 Graphical PK / PD Analysis Graphical PK / PD analysis included patients with high IFNGS who had at least one PD measurement before discontinuation in all treatment groups and at least one quantifiable serum PK observation in the anifrolumab 150 mg and 300 mg groups. Patients treated with anifrolumab had individual predicted mean anifrolumab concentrations (C) over the treatment period at anifrolumab 150 mg or anifrolumab 300 mg, respectively. ave ) were categorized according to median or tertiles (depending on sample size). Median 21-IFNGS PD neutralization over the 52-week treatment period was calculated as C ave Comparisons were made across subgroups.

[0203] PK / PD Modeling The population for the PK / PD modeling analysis included patients with high IFNGS who had baseline and at least one post-baseline PD measurement before discontinuation in all groups, and at least one quantifiable serum PK observation in the anifrolumab group. The relationship between anifrolumab exposure (PK) and PD neutralization of 21-IFNGS was described by an indirect response model in which the production of type I IFN-inducible genes was inhibited by anifrolumab. This model was the first nonlinear mixed-effects model developed to describe the PK / PD relationship of anifrolumab in patients with systemic sclerosis. A schematic diagram of the model is shown in Figure 16. The PK / PD model was implemented in the software NONMEM (version 7.3 or higher, ICON Development Solutions, Ellicott City, MD; 2006) to obtain PK / PD parameter estimates. Visual post-hoc predictive performance assessment was performed to ensure that the observed data were adequately captured by the 95% prediction intervals generated based on 5,000 model simulations.

[0204] 10.3.7. PD / Efficacy Analysis PD / efficacy analyses included patients with high IFNGS who had baseline and at least one post-baseline PD assessment before discontinuation. Individual median 21-IFNGS neutralization from baseline to steady-state levels was calculated over weeks 12, 24, 36, and 52 based on pooled observational data from the anifrolumab 150 mg and 300 mg treatment groups, excluding PD measurements collected after discontinuation. Patients in the pooled anifrolumab 150 mg and 300 mg treatment groups were divided into subgroups according to median 21-IFNGS neutralization quartile percentages. BICLA and SRI(4) response rates at week 52 were calculated for subquartile groups and the overall placebo treatment group.

[0205] 10.4.Results 10.4.1 Demographic data and baseline characteristics from IFNGS In the TULIP-1 and TULIP-2 trials, 819 patients received at least one dose of anifrolumab 300 mg, anifrolumab 150 mg, or placebo, and 676 (82.5%) and 143 (17.5%) had 4-gene type I IFNGS high and low, respectively. The 4 genes in the dichotomous 4-gene IFNGS test are a subset of the contiguous 21-IFNGS. 19、27 , 4-gene IFNGS status (high vs. low) was strongly correlated with the median 21-IFNGS score, which was 15.1 in patients with high IFNGS and 1.1 in patients with low IFNGS (Table 10-1, Figure 17).

[0206] [Table 11]

[0207] Baseline characteristics of type I high IFNGS and low IFNGS patients are shown in Table 10-1. High IFNGS patients were younger than low IFNGS patients (median age 40 vs. 46 years). A negative association between age and IFNGS expression was observed for both the dichotomous IFNGS test at screening and the median 21-IFNGS score at baseline (Figure 18). Compared with other geographic regions, North American patients were slightly older (median age 44 vs. 40-41 years) and slightly less likely to have high IFNGS (72.6% vs. 88.5%-90.9%). The proportion of patients with high IFNGS was higher in Black / African American patients (86.1%) and Asian patients (95.2%) than in North American-driven Caucasian patients (78.3%).

[0208] Patients with high IFNGS had more severe disease than patients with low IFNGS, with higher rates of anti-dsDNA seropositivity (48.7% vs. 25.9%), C3 abnormalities (41.7% vs. 13.3%), and C4 abnormalities (26.9% vs. 5.6%) at baseline, and more patients had a SLEDAI-2K score ≥ 10 (71.9% vs. 62.9%) (Table 10-1). The association between disease severity and IFNGS was also reflected in the placebo group, with a significant difference in the TULIP-1 and TULIP-2 protocols. 16、17 The prevalence of prohibited drug use by week 52 was higher in patients with high IFNGS than in patients with low IFNGS (34.1% vs. 18.8%); in contrast, patients with high IFNGS receiving anifrolumab 300 mg had a similar rate of prohibited drug use to patients with low IFNGS (approximately 21%).

[0209] 10.4.2.PK / PD Analysis The low IFNGS subgroup had baseline 21-IFNGS scores similar to healthy subjects, which were insufficient to observe significant PD neutralization, and therefore the median percentage neutralization of 21-IFNGS over time was minimal for both anifrolumab 300 mg and placebo in low IFNGS patients ( FIG. 19 ). Therefore, low IFNGS patients were not included in the PK / PD or PD / efficacy analyses.

[0210] [Table 12]

[0211] In contrast, in high-IFNGS patients treated with anifrolumab 300 mg, PD reversal of 21-IFNGS occurred across all baseline 21-IFNGS groups, but patients in the lowest quartile of baseline 21-IFNGS (with baseline 21-IFNGS closest to that observed in low-IFNGS patients) had lower PD reversal with greater variability compared to patients in the higher quartiles of baseline 21-IFNGS (Figure 20).

[0212] 10.4.2.1. PK / PD Graphical Analysis Graphical PK / PD analysis included 357 high-IFNGS patients from TULIP-1 who received placebo (n=144), anifrolumab 150 mg (n=72), or anifrolumab 300 mg (n=141), and 297 high-IFNGS patients from TULIP-2 who received placebo (n=149) or anifrolumab 300 mg (n=148) (Figure 21).

[0213] Patients treated with anifrolumab 300 mg were included in the C ave Patients treated with anifrolumab 150 mg had a median (11.5 μg mL ) of 1.5 μg mL due to the small sample size. -1 ) above or below the median C ave Patients treated with 300 mg of anifrolumab generally had higher C values ​​than patients treated with 150 mg of anifrolumab due to nonlinear PK exposure, as previously reported. ave values ​​and the observed C ave There was minimal overlap in values ​​(Table 10-2).

[0214] All anifrolumab 300mg C ave The lowest C tertile achieved a median PD reversal of approximately 80%, which was sustained from week 12 to week 52, but variability was observed across both studies. ave The tertile has two higher C ave The two highest C ave Tertiles had PD reversal plateauing at approximately 90%. SLEDAI-2K score (<10 vs. ≥10), oral glucocorticoid dosage (<10 vs. ≥10 mg / day) -1 Substantial and durable PD neutralization with anifrolumab 300 mg was consistently observed across baseline disease activity subgroups, including C ), and lupus serology (anti-dsDNA antibodies, C3 and C4) (Figure 22). In contrast, submedian C aveIn the subgroup of patients treated with anifrolumab 150 mg who had MAD values, PD reversal was highly variable (large MAD values) but numerically higher than the minimum PD reversal observed with placebo.

[0215] 10.4.2.2.PK / PD Modeling Analysis The PK / PD modeling analysis included 646 high-IFNGS patients from the pooled TULIP-1 and TULIP-2 trials who received placebo (n=289), anifrolumab 150 mg (n=70), or anifrolumab 300 mg (n=287). The PK / PD indirect response model adequately captured the observed data with a 95% prediction interval, as demonstrated by visual post-hoc predictive performance assessment (Figure 23). Diagnostic plots of NONMEM output are shown in Figures 25A-D. PK / PD model parameter estimates are shown in Table 10-3.

[0216] I C 80 was defined as the estimated anifrolumab concentration required to obtain 80% of the maximal inhibition of 21-IFNGS expression relative to baseline. The model was based on 3.88 μg mL -1 IC 80 This resulted in an estimated IC of 6.56 nM. 50 Based on estimated values ​​and the molecular weight of anifrolumab of 148 kDa. トラフ The estimated median β-amylindrome was higher with anifrolumab 300 mg than with anifrolumab 150 mg (15.6 vs. 0.2 μg / mL) due to nonlinearity. -1 ) (Figure 24). Thus, a higher proportion of patients treated with 300 mg of anifrolumab compared with 150 mg (approximately 83% vs. approximately 27%) had C トラフ IC 80 The baseline 21-IFNGS score estimated by the model was 13.1 in patients with high IFNGS (Table 10-3).

[0217] [Table 13]

[0218] 10.4.3. PD Reversal in Pooled Anifrolumab 150 mg and 300 mg Groups 341 patients with high IFNGS who received anifrolumab 150 mg or 300 mg were classified according to PD neutralization quartile (Q1 <51.7%, Q2 ≥51.7%-85.3%, Q3 ≥85.3%-92.6%, Q4 ≥92.6%). Patients in the anifrolumab 300 mg group were primarily in the higher PD neutralization quartiles (Q2-Q4), with median PD neutralization from weeks 12 to 52 of >86% with anifrolumab 300 mg compared with <37% with anifrolumab 150 mg.

[0219] Of the 273 high-IFNGS patients from the anifrolumab 300 mg group included in the PD neutralization analysis, 41 (15.0%) were in the lowest quartile of PD neutralization (<51.7% neutralization). Of these 41 patients, 18 (43.9%) had baseline 21-IFNGS scores in the lowest quartile (Q1<3.8), which were associated with lower PD neutralization (Figure 20). The remaining 23 patients tended to have low PK exposure, with 19 having the lowest anifrolumab 300 mg PK C ave In the middle quartile (C ave <27.6 μg / mL -1 ), and four were in the second quartile (27.6-39.2 μg / mL -1 ) (Pooled TULIP-1 and TULIP-2 Anifrolumab 300mg PK C ave (Quartiles are shown in Table 10-4.) Compared with the total high-IFNGS population (n=676), these 23 patients tended to have more active baseline disease, with a numerically higher proportion of patients reporting positive anti-dsDNA antibodies (56.2% vs. 48.7%), low C3 (56.5% vs. 41.7%), low C4 (47.8% vs. 26.9%), SLEDAI-2K score ≥ 10 (78.2% vs. 71.9%), or higher oral glucocorticoid dosage (12.4 vs. 10.2 mg / day). -1 )

[0220] [Table 14]

[0221] 10.4.4. PD / Efficacy Analysis The PD / efficacy analysis included 341 high-IFNGS patients who received anifrolumab 150 mg or 300 mg and 280 patients who received placebo. The PD / efficacy analyses are shown in Figures 26A and 26B. The proportion of patients with a BICLA response at week 52 increased with higher PD neutralization in the anifrolumab group (Q1 37.6%, Q2 49.4%, Q3 51.8%, Q4 58.1%); response rates in all anifrolumab quartiles were numerically higher than placebo (30%). Similarly, the proportion of patients with an SRI(4) response at week 52 increased in the PD-neutralization subgroup in the anifrolumab group (Q1 48.2%, Q2 56.5%, Q3 58.8%, Q4 64.0%); response rates in all anifrolumab quartiles were numerically higher than placebo (40%).

[0222] Next, we investigated whether there was a relationship between the BICLA response rate at week 52 and the baseline 21-IFNGS score. In the anifrolumab 300 mg group, the BICLA response rate at week 52 was numerically higher in patients with a high baseline 21-IFNGS score (Q4 ≥ 20.7) compared with patients with a low 21-IFNGS score (Q1 < 3.8) (TULIP-1: 54% vs. 40%; TULIP-2: 47% vs. 43%). However, across all baseline 21-IFNGS score quartiles in TULIP-1 and TULIP-2, the BICLA response was higher with anifrolumab 300 mg than with placebo (Figure 27).

[0223] 10.5. Discussion Correlating drug concentrations, pharmacodynamics, and efficacy can provide important insights into the relationship between a drug's mechanism of action and clinical response. In this analysis, we evaluated pooled data from the Phase 3 TULIP-1 and TULIP-2 trials in patients with moderate-to-severe SLE to examine the PK / PD and PD / efficacy relationships of anifrolumab. This study identified an association between anifrolumab serum concentrations and PD neutralization of type I IFN-inducible genes (21-IFNGS), which was subsequently linked to improved efficacy at week 52 in patients with high IFNGS at screening. This finding supports anifrolumab's mechanism of action: blocking the type I IFN pathway and inhibiting downstream gene expression that propagates SLE disease activity and drives lupus pathogenesis, thereby improving measures of disease activity and clinical efficacy.

[0224] Because PD neutralization was not significant in patients with low IFNGS at screening, only patients with high IFNGS were included in the analysis. Furthermore, it was important to specifically consider patients with high IFNGS because they have a higher anifrolumab clearance rate than patients with low IFNGS. IFNGS expression was associated with more active, treatment-resistant disease, increased serum concentrations of IFN-α, and serum markers of inflammation and immune dysregulation, including tumor necrosis factor (IL-2), IFN-γ, and IL-1R2. Consistently, compared with patients with low IFNGS, patients with high IFNGS had higher baseline disease activity, and more patients were seropositive for anti-dsDNA antibodies or had abnormal C3 / C4 ratios at baseline. In the placebo group, patients with high IFNGS were more likely to use prohibited drugs throughout the study than patients with low IFNGS. However, treatment with 300 mg of anifrolumab was associated with a reduction in the rate of prohibited drug use in patients with high IFNGS, similar to that observed in patients with low IFNGS. Discontinuation rates were lower with anifrolumab 300 mg than with placebo in both high-IFNGS and low-IFNGS patients.

[0225] The PK / PD model, IFNAR1 internalization kinetics, and information from the SLE study appeared robust, as estimates were consistent with observed data. The model-predicted parameters demonstrated a strong PK / PD relationship. Approximately 83% of patients in the anifrolumab 300 mg group were predicted to have anifrolumab trough concentration capable of inducing >80% inhibition of 21-IFNGS expression. Indeed, rapid (by week 12), substantial (approximately 80%), and sustained (by week 52) neutralization of 21-IFNGS was observed in all anifrolumab 300 mg C ave In contrast, only approximately 27% of patients in the anifrolumab 150 mg group expected to have anifrolumab trough concentration capable of inducing >80% inhibition of 21-IFNGS. Therefore, C ave In patients with PD, lower, more variable, and delayed PD neutralization was observed with anifrolumab 150 mg, where PD neutralization was minimal and similar to that observed with placebo. Lower anifrolumab serum exposure resulted in a more variable PD neutralization profile across studies and dosing regimens.

[0226] A small subset (15%) of high-IFNGS patients in the anifrolumab 300 mg group did not experience high PD reversal throughout the study (median baseline 21-IFNGS reversal percentage was less than 51.7%). Despite being assigned high-IFNGS status due to the dichotomous nature of the 4-gene IFNGS test, nearly half of these patients had baseline 21-IFNGS scores in the lowest quartile, and therefore did not require high PD reversal to achieve a 21-IFNGS score similar to healthy controls. The other half of these patients had low PK exposure, supporting a PK / PD relationship, and also tended to have numerically higher disease activity at baseline. However, measures of baseline disease activity did not appear to affect PD reversal with anifrolumab 300 mg across the pooled population, further supporting the anifrolumab IV 300 mg dosing regimen and corresponding 120 mg subcutaneous dose across patient subgroups, regardless of disease activity.

[0227] Consequently, although it may be suggested that a subset of patients with low PD neutralization may benefit from an anifrolumab dosage greater than 300 mg, there is no evidence to suggest that IV doses greater than 300 mg result in higher BICLA response rates. For example, in the Phase 2 MUSE study, the BICLA response rate at week 52 was higher with anifrolumab 300 mg (53.3%) than with anifrolumab 1000 mg (41.2%). Furthermore, analyses modeling the relationship between PK exposure and BICLA response rate in TULIP-1 and TULIP-2 predicted that anifrolumab 1000 mg would only provide additional benefit compared to anifrolumab 300 mg due to nonlinearity. However, as shown in Example 4: Determining the Optimal Subcutaneous Unit Dose, this variability combined with variability in bioavailability justifies surprisingly high subcutaneous doses greater than 105 mg.

[0228] PD neutralization of 21-IFNGS was associated with improved clinical efficacy. All anifrolumab PD neutralization quartiles had numerically higher BICLA and SRI(4) rates than the placebo group. However, the highest anifrolumab PD neutralization quartile had absolute BICLA and SRI(4) response rates that were approximately 21% and 16%, respectively, higher than the lowest anifrolumab PD neutralization quartile (consisting primarily of patients in the anifrolumab 150 mg group). These results are consistent with analyses of PK and efficacy associations in the TULIP-1 and TULIP-2 studies, which identified exposure / efficacy relationships and demonstrated that all anifrolumab PK subgroups had higher BICLA / SRI(4) response rates than the placebo group.

[0229] Early changes in PD markers associated with clinical efficacy at later time points are clinically beneficial. This study suggests that the degree of IFNGS neutralization could be used as an established PD marker in the design of future anifrolumab trials investigating various populations (e.g., pediatric patients or other lupus populations, such as those with lupus nephritis (LN) or cutaneous lupus erythematosus (CLE)), or with various administration methods, such as subcutaneous injection.

[0230] Anifrolumab 300 mg IV once every 4 weeks was selected as the optimal dosing regimen in patients with moderate to severe SLE due to its favorable benefit / risk profile in the phase 2 MUSE trial. ave was consistent throughout the study and was higher than the concentrations induced by anifrolumab 150 mg, with little overlap between subgroups, consistent with the nonlinear PK profile of anifrolumab. Steady-state concentrations of anifrolumab, as quantified by trough concentrations at week 24, were predicted to be approximately 80-fold higher with anifrolumab 300 mg than with anifrolumab 150 mg.

[0231] 10.6. Conclusion Herein, we elucidate the clear relationship between anifrolumab serum exposure and PD neutralization in patients with moderate to severe SLE despite receiving standard therapy, and provide evidence supporting the anifrolumab IV 300 mg Q4W dosing regimen and anifrolumab SC 120 mg QW dosing regimen. Indeed, anifrolumab 300 mg provided sufficient PK exposure for patients with high IFNGS, resulting in rapid, substantial, and sustained neutralization of 21-IFNGS, which was subsequently associated with improved clinical efficacy. Therefore, the same clinical efficacy is expected with anifrolumab SC doses greater than 105 mg QW, such as 120 mg.

[0232] 11. Example 7: Treatment of Type I IFN Disorders 11.1. Type I IFN Signature To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether a subject's disease is driven by type I IFN activation. However, direct measurement of type I IFN remains challenging. Therefore, transcript-based markers have been developed to assess the effect of overexpression of a target protein on a set of specific mRNA markers. Expression of these markers is easily detected in whole blood using, for example, PCR (e.g., TaqMan) assays.

[0233] Gene expression may be measured by RT-PCR. Suitable primers and probes for detecting genes can be found in WO2011028933. A suitable kit for measuring gene expression in the IFNGS test is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit) described in Brohawn et al.

[26] (which is incorporated herein by reference in its entirety). The 21-IFNGS assay consists of 21 type I IFN-α / β-inducible genes (Figure 28), including the four genes in the dichotomous IFNGS test, as described above [24, 25].

[0234] The bimodal distribution of transcript scores in SLE subjects (using a four-gene IFN test) helps define subpopulations with high and low IFN test results (Figure 29A). The type I IFN test is described in International Publication No. WO 2011028933A1, which is incorporated herein by reference in its entirety. The type I IFN gene signature can be used to identify subjects with high type I IFN gene signature (IFNGS) test results or low IFNGS test results (Figure 29B). The four-gene IFNGS test measures the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in a subject's whole blood relative to three reference genes: 18S, ACTB, and GAPDH. The result of the test is a score that is compared to pre-established cutoffs that classify patients into two groups: those with low or high levels of IFN-inducible gene expression (Figure 29B).

[0235] The type I IFN gene score demonstrates a correlation with expression in diseased tissues such as the skin in SLE. In particular, a high type I IFN gene signature is associated with high disease activity and OCS use in SLE (Figure 29C).

[0236] IFNGS can be used to identify other type I IFN-mediated diseases suitable for treatment with IFNAR1 inhibitors. Type I IFN-mediated diseases include lupus nephritis (LN) and Sjogren's syndrome, in which patients can be identified as having high IFNGS (Figures 31A and 31B). A similar core type I IFN signature (5-gene score) is activated in patients with SSc and myositis (Figure 32).

[0237] Lupus IFNGS (21 genes) in lupus (SLE) are neutralized by inhibitors of type I IFN signaling, such as the anti-IFN-α antibody sifalimumab (Figure 30A) or the type I IFN receptor (IFNAR1) inhibitor anifrolumab (Figure 30B). See also Section 10.

[0238] Scleroderma Systemic sclerosis (SSc) is a rare autoimmune disease characterized by chronic immune activation and excessive deposition of extracellular matrix components. A phase 1 dose-escalation trial (Study CP180) investigated the safety and tolerability of anifrolumab in subjects with SSc (Figure 33). The IFNGS score in SSc patients was determined to be the median fold change (FC) of five IFN-inducible genes that were among the most differentially regulated genes in scleroderma patients compared to healthy controls. The five genes are a subset of the 21-gene IFNGS.

[0239] The 5-gene IFNGS, as measured using a 5-gene signature (IFI27, RSAD2, IFI44, IFI44L, IFI6), is elevated in whole blood (WB) from scleroderma patients (Figure 31B). The 5-gene IFNGS score in SSc patients is comparable to that in SLE patients (Figures 32A, 34A). The baseline IFN signature is highly correlated between affected tissues and the periphery and with baseline disease activity (Figure 34B). There is also a positive correlation between the baseline 5-gene IFNGS score and SSc disease activity, as measured by the modified Rodnan skin score (mRTSS) (Figure 34C).

[0240] As described in International Publication WO 2013 / 188494 (incorporated herein by reference in its entirety), the five-gene IFNGS can be neutralized in scleroderma (SSc) patients (Figure 35A). Specifically, in Study CP180 (NCT0093082), approximately two-thirds of SSc patients were type I IFN signature-positive at baseline. Following treatment with anifrolumab, doses of 1 mg / kg (mpk) or higher (both single and multiple doses) resulted in rapid and near-complete suppression of IFNGS (day 1) (Figure 35B), accompanied by a clear dose-dependent effect in which the signature remained inhibited before recovery (Figures 35B and 35C). The IFN score used in Study CP180, similar to those used in other autoimmune indications, was identified as a sensitive PD marker associated with treatment with inhibitors of type I IFN-mediated signaling in SSc.

[0241] Anifrolumab treatment of SSc patients also suppressed T cell activation (via reduction of CXCL10 and CD40L) (Figure 36). Anifrolumab also suppressed markers of collagen formation and upregulated markers of collagen degradation (Figure 36), suggesting a mechanism of action through which inhibition of type I IFN signaling in SSc patients modulates tissue. There was further improvement in skin scores (mRSS at the highest dose).

[0242] In summary, treatment of scleroderma patients with anifrolumab shows dose-dependent and almost complete suppression of type I IFN score in WB and skin. Core IFN Glycine Serotectomy (IFNGS) is elevated in SSc patients, and treatment with anifrolumab neutralizes this gene signature. Anifrolumab has also been shown to have therapeutic effects in SSc patients. Therefore, anifrolumab is expected to have similar therapeutic effects in SSc patients as in SLE and LN patients at similar or the same anifrolumab doses shown to be safe and effective in SLE, i.e., 300 mg IV Q4W, or equivalent SC doses of more than 105 mg and less than 150 mg QW, especially 120 mg SC QW.

[0243] Myositis The presence of type I IFN in muscle biopsies from myositis was first observed by immunohistochemical studies

[27] , and subsequently, PDC was reported to be elevated in muscle and skin biopsies from dermatomyositis (DM) [28, 29]. The onset of DM or polymyositis (PM) has been observed to occur after IFN-α or IFN-β therapy, suggesting type I IFN as a potential therapeutic target in these two indications [30, 31]. IFN-β transcripts, but not IFN-α transcripts, were overexpressed in PM and dermatomyositis / JDM7. IFN-β is elevated in the blood of DM patients and correlates with type I IFN-inducible genes in the blood

[32] . Gene expression profiling analysis of muscle biopsies from myositis patients showed that the most overexpressed transcripts in DM patients compared with normal controls were IFN-α / β-inducible genes

[28] .

[0244] Compared to healthy volunteers (defined as a value <4), there is an overexpression of type I IFN-inducible genes (136 genes), particularly IFI44L and RSAD2, in the blood of patients with dermatomyositis (DM) or polymyositis (PM)

[11] . Greenberg et al. identified increased expression of 13 type I IFN signature PD markers, or IFI27, RSAD2, IFI44L, IFI44, OAS1, IFIT1, ISG15, OAS3, HERC5, MX1, ESPTI1, IFIT3, and IFI6, compared to healthy donors

[11] . In study MI-CP151 (NCT00533091), blood and muscle biopsy specimens were collected from patients. Baseline type I IFN gene signature (4-gene and 13-gene scores) levels were measured in muscle and blood of DM and PM patients, revealing elevated IFNGS scores in whole blood and muscle of both BM and PM patients (Figure 37, Figure 31A, Figure 38)

[10] . See also WO 2009 / 011770 and WO 2009 / 011770, both of which are incorporated herein by reference.

[0245] An inhibitor of type I IFN gene signaling (sifalimumab) neutralized the 13-gene IFNGS score in the blood and muscle of patients with DM and PM in a dose-dependent manner (Study MI-CP151, Figure 39). Notably, the type I IFN gene signature was maximally neutralized with a median of 91% in the 0.3 mg / kg cohort, with mean neutralization across all sifalimumab-treated cohorts of 47%, 33%, and 65%, observed at days 28, 56, and 98, respectively. At day 98, the four sifalimumab-treated cohorts demonstrated median neutralization of the gene signature ranging from 54% to 91%. Treatment of patients with myositis with sifalimumab demonstrated up to 80% neutralization of the type I IFN signature in muscle (Figure 38). A dose-dependent increase in IFNα suppression was observed across all four sifalimumab dose groups (0.3, 1.0, 3.0, and 10 mg / kg) compared with the placebo group. Inhibition of IFNα reduced immune cell infiltration into myositis muscle (DM and PM) (Figure 41). Sifalimumab suppressed downstream pathways of type I IFN in muscle from myositis patients, and target neutralization correlated with improved muscle function (MMT8) in myositis patients [10, 11] (Figure 42). Importantly, targeted modulation of the type I IFN gene signature in blood showed a correlational trend with disease activity in DM or PM patients (Figure 40A). Furthermore, targeted suppression of the type I IFN gene signature correlated with suppression of key disease-related signaling events in muscle tissue (Figure 40B).

[0246] In summary, core IFNGS genes are elevated in myositis patients, and treatment with sifalimumab neutralizes this gene signature. Therefore, the IFNGS signature data plausibly suggest that IFN pathway activation in myositis is within a similar range to SLE. Similar IFN activation is observed across SLE, DM, and PM (Figure 32). Furthermore, due to the ubiquitous nature of type I IFN receptors, common receptor availability is the most important factor for dose selection in myositis. The data indicate that similar PF / PD profiles exist across multiple disease states (e.g., comparing SLE and SSc). Furthermore, available subcutaneous dosing data from Studies 06 and 08 support the selection of a dose of approximately 120 mg SC QW in myositis. Anifrolumab completely suppressed type I IFN signaling via IFNAR, whereas sifalimumab only targets a large portion of IFN-α (Figure 43). Therefore, anifrolumab is expected to have similar neutralizing effects as sifalimumab against IFNGS in patients with myositis at similar or the same anifrolumab doses shown to be safe and effective in SLE, i.e., 300 mg IV Q4W, or equivalent SC doses greater than 105 mg and less than 150 mg QW, particularly 120 mg SC QW.

[0247] 12. Example 8: Injection Device Anifrolumab is administered by injection devices [1][9] such as prefilled syringes (PFS) (Figure 44A) or autoinjectors (AI) (Figure 44B).

[0248] 12.1.Autoinjector Anifrolumab may be administered by an auto-injector [1]. The auto-injector is shown in an exploded view (FIG. 45A) and in an assembled form (FIG. 45B). A label [4] is wrapped around or attached to the auto-injector [1] (FIG. 45C). The auto-injector has an auto-injector housing [3], a cap and cap remover [2], and a drive unit [5]. A unit dose [6] of a liquid anifrolumab formulation is contained within the auto-injector housing [3]. The unit dose [6] is visible through a viewing window [7].

[0249] 12.1.1.1. Prefilled syringes with accessories Anifrolumab may be administered via an accessory prefilled syringe (APFS) [8]. The APFS [8] contains a unit dose of anifrolumab [6] contained within a primary container [9], shown assembled in FIG. 46A and exploded in FIG. 46B. The primary container [9] has a plunger stopper

[16] . The primary container has a nominal fill volume

[17] of 0.8 ml but may contain slightly more than 0.8 ml. The remainder of the space within the primary container [9] is occupied by an air bubble

[18] . The air bubble

[18] may have a size of 3-5 mm, optionally 4 mm. The primary container [9] has a defined stopper position

[19] .

[0250] The primary container [9] of the accessory prefilled syringe (APFS) is provided within a PFS assembly [8], which includes a needle guard

[12] , a finger flange

[11] , and a plunger rod

[13] . A label

[14] is provided with the primary container [9] within the PFS assembly [8]. The label

[14] is wrapped around the syringe [9] in a label placement location

[15] .

[0251] Packaging An injection device [1] [8] is provided in the kit

[20] (Figure 47). A label [4]

[14] is provided with the APFS or auto-injector in packaging. The label contains instructions for use of the injection device [1], [8]. The packaging contains a tamper seal.

[0252] For example, the present disclosure provides the following embodiments. [1] A unit dose for subcutaneous administration containing more than (>) 105 mg and less than (<) 150 mg of a type I IFN receptor (IFNAR1) inhibitor. [2] 1. The unit dose according to claim 1, comprising 135 mg or less of the IFNAR1 inhibitor. [3] 3. The unit dose according to claim 1 or 2, comprising about 120 mg of the IFNAR1 inhibitor. [4] 1. The unit dose according to claim 1, consisting essentially of >105 mg and <150 mg of said IFNAR1 inhibitor. [5] 5. The unit dose of claim 4, consisting essentially of ≦135 mg of said IFNAR1 inhibitor. [6] 6. The unit dose of claim 5, consisting essentially of about 120 mg of the IFNAR1 inhibitor. [7] 7. The unit dose according to any one of 1 to 6, wherein the concentration of the IFNAR1 inhibitor is about 150 mg / ml. [8] 8. The unit dose according to any one of claims 1 to 7, wherein the volume of the unit dose is about 0.8 ml. [9] 9. The unit dose according to any one of claims 1 to 8, wherein the unit dose comprises a formulation of about 150 to 200 mg / ml of the IFNAR1 inhibitor, about 25 to 150 mM of a lysine salt, and an uncharged excipient.

[10] 10. The unit dose of claim 9, comprising a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05 w / v% polysorbate 80.

[11] 11. The unit dose of claim 9 or 10, wherein the formulation has a pH of about 5.9.

[12] 12. The unit dose according to any one of claims 1 to 11, wherein the IFNAR1 inhibitor is a human monoclonal antibody specific to IFNAR1, optionally a modified IgG1 class human monoclonal antibody.

[13] The antibody (a) heavy chain variable region complementarity-determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) heavy chain variable region complementarity-determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; c) heavy chain variable region complementarity-determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) light chain variable region complementarity-determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (e) a light chain variable region complementarity-determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and / or (f) light chain variable region complementarity-determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8 13. The unit dose according to claim 12, comprising:

[14] The antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. 14. The unit dose according to claim 12 or 13, comprising:

[15] 15. The unit dose of any one of claims 11 to 14, wherein the antibody comprises an Fc region comprising the amino acid substitution L234F as numbered by the EU index as set forth in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody, and optionally the antibody comprises amino acid substitutions in the Fc region of L235E and / or P331S as numbered by the EU index as set forth in Kabat.

[16] The antibody comprises (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11, and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12. 16. The unit dose according to any one of claims 12 to 15, comprising:

[17] 17. The unit dose according to any one of 1 to 16, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

[18] 18. A method for treating a type I interferon (IFN)-mediated disease in a subject, comprising subcutaneously administering a unit dose described in any one of claims 1 to 17 to a subject having a type I interferon (IFN)-mediated disease.

[19] A method for treating a type I IFN-mediated disease in a subject, comprising subcutaneously administering to the subject one dose of an IFNAR1 inhibitor, wherein the dose is greater than (>) 105 mg and less than (<) 150 mg.

[20] A method for treating a type I IFN-mediated disease in a subject, comprising subcutaneously administering one dose of an IFNAR1 inhibitor, wherein administering the dose subcutaneously once a week provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of the IFNAR1 inhibitor once every four weeks. [twenty one] 21. The method of claim 20, wherein subcutaneous administration of the dose once a week provides a plasma concentration in the subject that exceeds the plasma concentration provided by intravenous administration of 300 mg of the IFNAR1 inhibitor once every four weeks. [twenty two] 22. The method according to any one of 18 to 21, wherein the dose is <150 mg of the IFNAR1 inhibitor. [twenty three] 23. The method according to any one of 18 to 22, wherein the dose is >105 mg of the IFNAR1 inhibitor. [twenty four] 24. The method according to any one of 18 to 23, wherein the dose is administered subcutaneously in a single administration step. [twenty five] 25. The method according to any one of 18 to 24, wherein the dose of the IFNAR1 inhibitor is 135 mg or less (≦).

[26] 26. The method according to any one of 18 to 25, wherein the dose is about 120 mg of the IFNAR1 inhibitor.

[27] 27. The method of any one of 18 to 26, comprising administering the dose or unit dose subcutaneously every 6 to 8 days.

[28] 28. The method of any one of 18 to 27, comprising administering said dose or unit dose subcutaneously once per week (QW).

[29] 29. The method according to any one of claims 18 to 28, wherein the dose or unit dose is 120 mg of the IFNAR1 inhibitor, and the method comprises administering the dose subcutaneously in a single administration step once per week (QW).

[30] 30. The method of any one of 18 to 29, wherein the dose or unit dose is administered subcutaneously once a week for at least about 4, 8, 12, 16, 20, 24, 28, or 32 weeks.

[31] 31. The method of any one of 18 to 30, wherein the dose or unit dose is administered subcutaneously once a week for at least about 8 weeks.

[32] 32. The method according to any one of 18 to 31, wherein the dose or unit dose has a volume of about 0.5 to about 1 ml.

[33] 33. The method of any one of 18 to 32, wherein the dose or unit dose has a volume of about 0.8 ml.

[34] 34. The method of any one of 18 to 33, comprising administering a corticosteroid to the patient, optionally wherein the corticosteroid is an oral corticosteroid.

[35] 35. The method of claim 34, comprising administering an initial dose of the corticosteroid, followed by administering a second dose of the corticosteroid, wherein the second dose of the corticosteroid is less than the initial dose of the corticosteroid.

[36] 36. The method of claim 35, wherein the second dose of the corticosteroid is less than or equal to about a 7.5 mg prednisone equivalent dose, optionally wherein the second dose of the corticosteroid is less than or equal to a 5 mg prednisone equivalent dose, and optionally wherein the method comprises administering the second dose of the corticosteroid once daily.

[37] 37. The method of any one of claims 35 to 36, wherein the initial dose of the corticosteroid is about a 10 mg prednisone equivalent dose.

[38] 38. The method of any one of 35 to 37, comprising administering the second dose of the corticosteroid once daily.

[39] 39. The method of any one of 35 to 38, wherein the second dose of the corticosteroid is administered for at least 24 weeks, optionally for at least 28 weeks.

[40] 40. The method of any one of 18 to 39, wherein administration of the dose or unit provides a plasma concentration of the IFNAR1 inhibitor in the subject of ≧10 μg of anifrolumab or a functional variant thereof per ml of plasma (≧10 μg / ml).

[41] 41. The method of any one of 18 to 40, wherein administration of the dose or unit dose provides a plasma concentration of the IFNAR1 inhibitor in the subject of about 10 to 100 μg / ml, optionally about 20 to 80 μg / ml, optionally about 30 to 70 μg / ml.

[42] 42. The method of any one of 18 to 41, wherein administration of the dose or unit dose provides a trough concentration of the IFNAR1 inhibitor in the subject of ≧20 μg / ml, optionally ≧30 μg / ml, optionally ≧40 μg / ml.

[43] 43. The method of any one of 18 to 42, wherein administration of the dose or unit dose provides a trough concentration of the IFNAR1 inhibitor in the subject of about 20 to 100 μg / ml, optionally about 30 to 80 μg / ml, optionally about 40 to 70 μg / ml.

[44] 44. The method of any one of 18 to 43, wherein the subject is a patient with a high type I interferon-stimulated gene signature (IFNGS) test result prior to administration of the dose or unit dose, and optionally, the IFNGS is a 4-gene, 5-gene, or 21-gene IFNGS.

[45] 45. The method of any one of 18 to 44, comprising identifying the subject as a patient with a high IFNGS test result prior to treatment with the dose or unit dose.

[46] 46. ​​The method of any one of 18 to 45, wherein the dose or unit dose provides a therapeutic effect in the subject that is at least equivalent to the therapeutic effect provided by administration of an intravenous dose of 300 mg of the IFNAR1 inhibitor administered once every four weeks (Q4W).

[47] 47. The method of any one of 18 to 46, wherein the dose or unit dose provides a trough concentration of the IFNAR1 inhibitor in the subject that exceeds the trough concentration of the IFNAR1 inhibitor provided by administration of a 300 mg intravenous dose of anifrolumab or a functional variant thereof once every four weeks (Q4W).

[48] 48. The method according to any one of 18 to 47, wherein the IFNAR1 inhibitor is contained in a pharmaceutical composition.

[49] 49. The method of claim 48, wherein the pharmaceutical composition comprises 150 mg / mL of the IFNAR1 inhibitor, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[50] 49. The method of any one of claims 18 to 49, wherein the type I IFN-mediated disease is associated with a higher IFNGS score compared to a healthy donor, and the IFNGS score is a 4-gene, 5-gene, and / or 21-gene score.

[51] 51. The method according to any one of 18 to 50, wherein the type I IFN-mediated disease is an autoimmune disease.

[52] 52. The method according to any one of 18 to 51, wherein the type I IFN-mediated disease is lupus.

[53] 53. The method of claim 52, wherein the type I IFN-mediated disease is systemic lupus erythematosus (SLE), and optionally, the SLE is moderate to severe active autoantibody-positive SLE.

[54] 53. The method of claim 52, wherein the type I IFN-mediated disease is lupus nephritis (LN).

[55] 53. The method of claim 52, wherein the type I IFN-mediated disease is cutaneous lupus erythematosus (CLE).

[56] 56. The method of any one of 52 to 55, wherein administration of the dose or unit dose results in an improvement from baseline in the patient's BILAG-based Composite Lupus Assessment (BICLA) response rate.

[57] 57. The method of any one of 52 to 56, wherein administration of the dose or unit dose results in an improvement of 4 points from baseline in the patient's Systemic Lupus Erythematosus Responder Index (SRI).

[58] 58. The method according to any one of 52 to 57, wherein the method reduces SLE disease activity in the subject.

[59] Reducing SLE disease activity in the subject a) BILAG-Based Composite Lupus Assessment (BICLA) response in said subject; b) the SRI(4) response in said subject, and / or 59. The method of claim 58, comprising: c) reducing the subject's Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score compared to the subject's CLASI score before treatment.

[60] 52. The method of claim 51, wherein the type I IFN-mediated disease is myositis.

[61] 52. The method of claim 51, wherein the type I IFN-mediated disease is scleroderma.

[62] 52. The method of claim 51, wherein the type I IFN-mediated disease is Sjogren's syndrome.

[63] The method according to any one of 18 to 62, wherein the IFNAR1 inhibitor neutralizes the elevated IFNGS in the subject.

[64] 64. The method according to any one of 18 to 63, wherein the IFNAR1 is a human monoclonal antibody specific to IFNAR1, optionally a modified IgG1 class human monoclonal antibody.

[65] The antibody a) heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) heavy chain variable region complementarity-determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; c) heavy chain variable region complementarity-determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) light chain variable region complementarity-determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (e) a light chain variable region complementarity-determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and / or (f) The unit dose described in 64, comprising a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[66] 66. The unit dose of claim 64 or 65, wherein the antibody comprises (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

[67] 66. The method of claim 64 or 65, wherein the antibody comprises an Fc region comprising the amino acid substitution L234F as numbered by the EU index as set forth in Kabat, and the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody.

[68] 67. The unit dose according to any one of claims 64 to 66, wherein the antibody comprises (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11, and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[69] 69. The method according to any one of 18 to 68, wherein the IFNAR1 inhibitor is anifrolumab or a functional variant thereof.

[70] 20. The method of claim 19, wherein the type I IFN-mediated disease is SLE, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, the dose is 120 mg, and the method comprises administering the dose subcutaneously once a week.

[71] 20. The method of claim 19, wherein the type I IFN-mediated disease is LN, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, the dose is 120 mg, and the method comprises administering the dose subcutaneously once a week.

[72] 20. The method of claim 19, wherein the type I IFN-mediated disease is CLE, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, the dose is 120 mg, and the method comprises administering the dose subcutaneously once a week.

[73] 20. The method of claim 19, wherein the type I IFN-mediated disease is myositis, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, the dose is 120 mg, and the method comprises administering the dose subcutaneously once a week.

[74] 20. The method of claim 19, wherein the type I IFN-mediated disease is scleroderma, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, the dose is 120 mg, and the method comprises administering the dose subcutaneously once a week.

[75] 20. The method of claim 19, wherein the type I IFN-mediated disease is Sjogren's syndrome, the IFNAR1 inhibitor is anifrolumab or a functional variant thereof, the dose is 120 mg, and the method comprises administering the dose subcutaneously once a week.

[76] A pharmaceutical composition for use in the method of treatment of any one of claims 18 to 75, wherein the method comprises subcutaneously administering the pharmaceutical composition to the subject, and the pharmaceutical composition comprises a unit dose of any one of claims 1 to 17.

[77] 1. A pharmaceutical composition for use in a method for treating a type I IFN-mediated disease in a subject, said method comprising subcutaneously administering said pharmaceutical composition to the subject, said pharmaceutical composition comprising a dose of anifrolumab or a functional variant thereof, said dose being greater than (>) 105 mg and less than (<) 150 mg.

[78] 78. A pharmaceutical composition for use according to claim 76 or 77, wherein the dose is about 120 mg of anifrolumab or a functional variant thereof.

[79] 79. An injection device comprising a unit dose according to any one of claims 1 to 17 or a pharmaceutical composition for use according to any one of claims 76 to 78.

[80] 79. The injection device according to claim 79, which is a pre-filled syringe (PFS).

[81] 79. The injection device according to claim 79, which is an accessory pre-filled syringe (AFPS).

[82] 79. The injection device according to claim 79, which is an automatic injector.

[83] 82. A kit comprising: i) a unit dose according to any one of claims 1 to 17; ii) a pharmaceutical composition according to any one of claims 77 or 78; or iii) an injection device according to any one of claims 79 to 82; and instructions for use, wherein the instructions for use include instructions for subcutaneously administering the unit dose or pharmaceutical composition to a subject.

[84] 84. The kit of claim 83, wherein the instructions for use specify that the unit dose or pharmaceutical composition is for use in any of the methods described in any one of claims 18 to 75.

[85] 85. The kit of claim 83 or 84, comprising packaging configured to hold the injection device and the instructions for use.

[86] 86. The kit according to any one of 83 to 85, wherein the instruction manual is attached to the injection device.

[87] 87. The kit of any one of claims 83 to 86, wherein the instructions for use include instructions for administering 120 mg of anifrolumab or the functional variant.

[88] 88. The kit of any one of claims 83 to 87, wherein the instructions for use include instructions for subcutaneously administering 120 mg of anifrolumab or the functional variant once weekly.

[89] 88. The kit according to any one of claims 83 to 87, wherein the instructions for use include instructions for use in accordance with the method according to any one of claims 18 to 75. References All publications mentioned herein and / or in the references below are hereby incorporated by reference. [1]MRTurner and SVBalu-Iyer, J.Pharm.Sci.107,1247(2018). [2] B. Bittner, W. Richter, and J. Schmidt, Biodrugs 32, 425 (2018). [3] J. Witcher et al., Br. J. Clin. Pharmacol. 81, 908 (2016). [4]DAIsenberg et al.,Ann.Rheum.Dis.75,323(2016). [5]JTMerrill et al.,Ann.Rheum.Dis.75,332(2016). [6] GTFerguson et al., J. Asthma Allergy 11,63(2018). [7] M.Khamashta et al.,Ann.Rheum.Dis.75,1909(2016). [8] R. Tummala et al., Lupus Sci. Med. 5, e000252 (2018). [9] A. Psarras, P. Emery, and EMVital, Rheumatol. Oxf. Engl. 56, 1662 (2017).

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Claims

1. An injection device containing a pharmaceutical composition for use in a method for treating a disease in a subject, wherein the pharmaceutical composition comprises more than (>) 105 mg and less than (<) 150 mg of a type I IFN receptor (IFNAR1) inhibitor, the method comprising subcutaneously administering more than (>) 105 mg and less than (<) 150 mg of the IFNAR1 inhibitor to the subject once per week (QW), and the IFNAR1 inhibitor is anifrolumab.

2. 2. The injection device of claim 1, wherein the pharmaceutical composition comprises 135 mg or less of the IFNAR1 inhibitor.

3. 2. The injection device of claim 1, wherein the pharmaceutical composition comprises 120 mg of the IFNAR1 inhibitor.

4. An injection device as described in claim 1, wherein the disease is a type I interferon (IFN)-mediated disease.

5. The injection device of claim 4, wherein the disease is an autoimmune disease.

6. 5. The injection device of claim 4, wherein the disease is lupus.

7. 5. The injection device of claim 4, wherein the disease is systemic lupus erythematosus (SLE).

8. 7. The injection device of claim 6, wherein the disease is lupus nephritis (LN) or cutaneous lupus erythematosus (CLE).

9. The injection device of claim 5, wherein the disease is myositis.

10. 6. The injection device of claim 5, wherein the disease is scleroderma or Sjogren's syndrome.

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